Systems and methods for applying and monitoring eye therapy

ABSTRACT

Devices and approaches for activating cross-linking within corneal tissue to stabilize and strengthen the corneal tissue following an eye therapy treatment. A feedback system is provided to acquire measurements and pass feedback information to a controller. The feedback system may include an interferometer system, a corneal polarimetry system, or other configurations for monitoring cross-linking activity within the cornea. The controller is adapted to analyze the feedback information and adjust treatment to the eye based on the information. Aspects of the feedback system may also be used to monitor and diagnose features of the eye  1 . Methods of activating cross-linking according to information provided by a feedback system in order to improve accuracy and safety of a cross-linking therapy are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to: U.S. Provisional Application No.61/315,840, filed Mar. 19, 2010; U.S. Provisional Application No.61/319,111, filed Mar. 30, 2010; U.S. Provisional Application No.61/326,527, filed Apr. 21, 2010; U.S. Provisional Application No.61/328,138, filed Apr. 26, 2010; U.S. Provisional Application No.61/377,024, filed Aug. 25, 2010; U.S. Provisional Application No.61/388,963, filed Oct. 1, 2010; U.S. Provisional Application No.61/409,103, filed Nov. 1, 2010; and U.S. Provisional Application No.61/423,375, filed Dec. 15, 2010, the contents of each of theseapplications being incorporated entirely herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention pertains to systems and methods for stabilizing cornealtissue, and more particularly, systems and methods for applying andactivating a cross-linking agent in corneal tissue and monitoring theactivation of the cross-linking agent.

2. Description of Related Art

A variety of eye disorders, such as myopia, keratoconus, and hyperopia,involve abnormal shaping of the cornea. Laser-assisted in-situkeratomileusis (LASIK) is one of a number of corrective procedures thatreshape the cornea so that light traveling through the cornea isproperly focused onto the retina located in the back of the eye. DuringLASIK eye surgery, an instrument called a microkeratome is used to cut athin flap in the cornea. The cornea is then peeled back and theunderlying cornea tissue ablated to the desired shape with an excimerlaser. After the desired reshaping of the cornea is achieved, the corneaflap is put back in place and the surgery is complete.

In another corrective procedure that reshapes the cornea,thermokeratoplasty provides a noninvasive procedure that applieselectrical energy in the microwave or radio frequency (RF) band to thecornea. In particular, the electrical energy raises the cornealtemperature until the collagen fibers in the cornea shrink at about 60°C. The onset of shrinkage is rapid, and stresses resulting from thisshrinkage reshape the corneal surface. Thus, application of energyaccording to particular patterns, including, but not limited to,circular or annular patterns, may cause aspects of the cornea to flattenand improve vision in the eye.

The success of procedures, such as LASIK or thermokeratoplasty, inaddressing eye disorders, such as myopia, keratoconus, and hyperopia,depends on the stability of the changes in the corneal structure afterthe procedures have been applied.

BRIEF SUMMARY

Embodiments according to aspects of the present disclosure providesystems and methods for stabilizing corneal tissue and improving itsbiomechanical strength, particularly after desired structural changeshave been achieved in the corneal tissue. For example, the embodimentshelp to preserve the desired reshaping of the cornea produced by LASIKsurgery, thermokeratoplasty, or other similar treatments.

According to aspects of the present disclosure, after a treatmentproduces a desired change to the shape of a cornea, a cross-linkingagent is activated in the treated region of the cornea. Thecross-linking agent prevents the corneal fibrils in the treated regionsfrom moving and causing undesired changes to the shape of the cornea. Aninitiating element may be applied to the treated corneal fibrils toactivate the cross-linking agent.

In some embodiments, for example, the cross-linking agent may beRiboflavin and the initiating element may be photoactivating light, suchas ultraviolet (UV) light. In these embodiments, the photoactivatinglight initiates cross-linking activity by irradiating the appliedcross-linking agent to release reactive oxygen radicals in the cornealtissue. In particular, the cross-linking agent, e.g., Riboflavin, actsas a sensitizer to convert O₂ into singlet oxygen which causescross-linking within the corneal tissue.

The initiating element may be applied according to a selected pattern tostabilize and strengthen the regions of the cornea where structuralchanges have been generated by the treatment. Accordingly, aspects ofthe present disclosure may include a delivery system that accurately andprecisely delivers the initiating element to corneal fibrils accordingto a selected pattern. In embodiments where the initiating element is UVlight, the delivery system may deliver the UV light in the form of alaser.

In some embodiments, the UV light may be delivered with laser scanningtechnologies. Embodiments may also employ aspects of multiphotonexcitation microscopy. Advantageously, the use of laser scanningtechnologies allows cross-linking to be activated more effectivelybeyond the surface of the cornea, at depths where stronger and morestable corneal structure is desired. In particular, treatment maygenerate desired changes in corneal structure at the mid-depth region.The application of the initiating element is applied precisely accordingto a selected three-dimensional pattern and is not limited to atwo-dimensional area at the surface of the cornea. In general,embodiments stabilize a three-dimensional structure of corneal tissuethrough selective application and activation of cross-linking in thecorneal tissue.

Aspects of the present disclosure also provide devices, systems, andapproaches for monitoring the reshaping and strengthening of the cornealtissue, and for activating the cross-linking in the corneal tissue in aniterative approach. Additionally, some embodiments may employ a feedbacksystem to determine how to iteratively activate the cross-linking agentin the corneal tissue, and how to adjust subsequent activations of thecross-linking agent.

Aspects of the present disclosure provide a system for controllingactivation of a cross-linking agent applied to an eye. The systemincludes a feedback system, a controller, and a cross-linking activationsystem. The feedback system provides feedback information indicative ofa biomechanical strength of corneal tissue of the eye. The controllerreceives the feedback information and automatically determines anindication of an amount of cross-linking in the corneal tissue based onthe received feedback information. The cross-linking activation systeminitiates cross-linking in the corneal tissue according to one or morecontrol signals generated by the controller. The one or more controlsignals can be generated according to a function including thedetermined indication of the amount of cross-linking in the cornealtissue.

In some embodiments, the feedback system is an interferometer adapted tointerfere a beam of light reflected from a surface of the eye with areference beam of light reflected from a reference surface. Theinterfering beams of light can pass through a polarizing filter andcreate an intensity pattern detected by a camera associated with thefeedback system. The feedback information can be an output from theassociated camera. The feedback system can also include a distancemeasurement system for monitoring a distance between the eye and theinterferometer and provide an indication of the monitored distance tothe controller. The associated camera can be adapted to detect aplurality of intensity patterns and the controller can be furtheradapted to: receive the plurality of detected intensity patterns;determine a plurality of surface profiles of the surface of the eyeassociated with the plurality of detected intensity patterns based onthe plurality of detected intensity patterns and based on the monitoreddistance; and determine an amount of dynamic deformation of the surfaceof the eye based on the determined plurality of surface profiles.

Aspects of the present disclosure further provide a method forcontrollably activating a cross-linking agent applied to an eye. Themethod includes receiving feedback information including electronicsignals output from a feedback system adapted to monitor the eye. Thefeedback information is indicative of a biomechanical strength ofcorneal tissue of the eye. The method also includes automaticallyanalyzing the feedback information to determine a dosage of light to beapplied to the eye. The method also includes activating thecross-linking agent by conveying light to the eye according to thedetermined dosage. The method may also include receiving targetinginformation indicative of an alignment of the eye with respect to theconveyed light. The method may also include automatically adjusting thealignment of the eye with respect to the conveyed light according to thereceived targeting information.

Aspects of the present disclosure further provide a method foractivating cross-linking in corneal tissue of an eye. The methodincludes applying a cross-linking agent having a first concentration tothe eye. The method also includes allowing, during a first diffusiontime, the cross-linking agent having the first concentration to diffusewithin the eye. The method also includes activating the cross-linkingagent with a photoactivating light applied according to a first dose,the first dose specified by a first power and a first bandwidth. Themethod also includes activating the cross-linking agent with thephotoactivating light applied according to a second dose, the seconddose specified by a second power and a second bandwidth.

Aspects of the present disclosure also provide a system for activating across-linking agent applied to a cornea of an eye. The system includes alight source for emitting photoactivating light sufficient foractivating cross-linking in the corneal tissue by exciting thecross-linking agent to produce a reactive singlet oxygen from oxygencontent in corneal tissue of the eye. The system also includes a mirrorarray having a plurality of minors arranged in rows and columns. Theplurality of minors are adapted to selectively direct thephotoactivating light toward the eye according to a pixelated intensitypattern having pixels corresponding to the plurality of mirrors in themirror array. The plurality of minors are alignable according to one ormore control signals. The system also includes a controller forproviding the one or more control signals to programmatically align theplurality of minors in the array of mirrors such that the pixelatedintensity pattern emerges from the minor array responsive to thephotoactivating light scanning across the plurality of minors.

Aspects of the present disclosure further include a method of activatinga cross-linking agent applied to an eye. The method includes emittingphotoactivating light sufficient for activating cross-linking in thecorneal tissue by exciting the cross-linking agent to produce a reactivesinglet oxygen from oxygen content in corneal tissue of the eye. Themethod also includes directing the photoactivating light to be scannedacross a mirror array having a plurality of minors arranged in rows andcolumns. The plurality of minors are adapted to selectively direct thephotoactivating light toward the eye according to a pixelated intensitypattern having pixels corresponding to the plurality of mirrors in themirror array. The plurality of minors are alignable according to one ormore control signals. The method also includes generating the one ormore control signals for programmatically aligning the plurality ofmirrors in the minor array according to the pixelated intensity pattern.

Aspects of the present disclosure also provide a system for activating across-linking agent applied to an eye. The system includes a lightsource for emitting photoactivating light sufficient for activatingcross-linking in the corneal tissue by exciting the cross-linking agentto produce a reactive singlet oxygen from oxygen content in cornealtissue of the eye. The system also includes a mask adapted toselectively allow the photoactivating light to be transmittedtherethrough. The regions of the mask allowing the photoactivating lightto be transmitted define a pattern of activation of the cross-linkingagent.

Aspects further provide a method of activating a cross-linking agentapplied to an eye. The method includes emitting photoactivating lightsufficient for activating cross-linking in the corneal tissue byexciting the cross-linking agent to produce a reactive singlet oxygenfrom oxygen content in corneal tissue of the eye. The method furtherincludes directing the photoactivating light to pass through a maskadapted to selectively allow the photoactivating light to be transmittedtherethrough. The regions of the mask allowing the photoactivating lightto be transmitted defining a pattern of activation of the cross-linkingagent.

Aspects further provide a system for monitoring an eye. The systemincludes an interferometer and a controller. The interferometer includesa light source for providing a beam of light having a referencepolarization state. The interferometer also includes a corneal imaginglens for directing a beam of light from the light source toward asurface of the eye and collimating light reflected from the surface ofthe eye. The interferometer also includes a reference surface forproviding a reference surface to compare with a surface of the eye. Theinterferometer also includes one or more beam splitters adapted to splitthe beam of light and direct a first portion to be reflected from thesurface of the eye, and direct a second portion to be reflected from thereference surface; and combine the reflected first portion and thereflected second portion to form a superimposed beam. The interferometeralso includes a polarizing filter, and a camera for capturing anintensity pattern of the superimposed beam emerging from the polarizingfilter. The controller analyzes the intensity pattern by determining aphase offset, for a plurality of points in the captured intensitypattern, between the reflected first portion and the reflected secondportion based on the captured intensity pattern. The controller furtheranalyzes the intensity pattern by determining an optical path lengthdifference between the reflected first portion and the reflected secondportion for the plurality of points from the phase offsets determinedfor the plurality of points. The controller further analyzes theintensity pattern by determining a surface profile of the eye bycomparing a profile of the reference surface to the optical path lengthdifferences determined for the plurality of points.

Aspects of the present disclosure further provide a method of monitoringan eye. The method includes emitting a beam of light from a light sourcehaving a known polarization. The method also includes splitting the beamand directing a first portion to be reflected from a surface of the eye,and directing a second portion to be reflected from a reference surface.The method also includes interfering the first portion of the beam andsecond portion of the beam to create a superimposed beam. The methodalso includes directing the superimposed beam through a polarizingfilter. The method also includes capturing an intensity pattern of thesuperimposed beam emerging from the polarizing filter. The method alsoincludes analyzing the captured intensity pattern to determine a surfaceprofile of the surface of the eye.

Aspects of the present disclosure further provide a system for applyinga controlled amount of cross-linking in corneal tissue of an eye. Thesystem includes an applicator adapted to apply a cross-linking agent tothe eye. The system also includes a light source adapted to emit aphotoactivating light. The system also includes a targeting systemadapted to create targeting feedback information indicative of aposition of a cornea of the eye. The system also includes a minor arrayhaving a plurality of minors arranged in rows and columns. The pluralityof minors are adapted to selectively direct the photoactivating lighttoward the eye according to a pixelated intensity pattern having pixelscorresponding to the plurality of mirrors in the mirror array. Thesystem also includes an interferometer adapted to monitor an amount ofcross-linking in the corneal tissue. The interferometer monitors theamount of cross-linking in the corneal tissue by interfering a beam oflight reflected from a surface of the eye with a reference beam of lightreflected from a reference surface. The interferometer monitors theamount of cross-linking in the corneal tissue by also capturing, via anassociated camera, a series of images of interference patterns due tooptical interference between the beam of light and the reference beam oflight. The series of images are indicative of a plurality of profiles ofthe surface of the eye. The system also includes a head restraint devicefor restraining a position of a head associated with the eye. The headrestraint device thereby aligns the eye with respect to theinterferometer. The system also includes a controller. The controller isadapted to receive the targeting feedback information and receive thegenerated series of intensity patterns. The controller is also adaptedto analyze the generated series of intensity patterns to determine theplurality of profiles of the surface of the eye associated therewith.The controller is also adapted to determine an amount of cross-linkingof the corneal tissue based on a dynamic deformation of the surface ofthe eye. The dynamic deformation of the eye is indicated by theplurality of profiles of the surface of the eye. The controller is alsoadapted to adjust the pixelated intensity pattern according to data. Thedata includes at least one of: the targeting feedback information andthe determined amount of cross-linking.

These and other aspects of the present disclosure will become moreapparent from the following detailed description of embodiments of thepresent disclosure when viewed in conjunction with the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a block diagram of an example delivery system fordelivering a cross-linking agent and an activator to a cornea of an eyein order to initiate molecular cross-linking of corneal collagen withinthe cornea.

FIG. 2A provides a flowchart showing an example embodiment according toaspects of the present disclosure for activating cross-linking withincornea tissue using a cross-linking agent and an initiating element.

FIG. 2B provides a flowchart similar to FIG. 2A where Riboflavin may beapplied topically as the cross-linking agent and UV light may be appliedas the initiating element.

FIG. 2C provides a flowchart similar to FIG. 2A, but with an additionalstep for placing a mask on the eye described in FIGS. 10A and 10B.

FIG. 3 provides an example delivery system for delivering light to thecornea 2 employing laser scanning technology.

FIG. 4 illustrates a delivery system incorporating a feedback system.

FIG. 5A illustrates a delivery system for activating cross-linking inthe cornea with the laser scanning device and having a video camerafeedback system.

FIG. 5B illustrates an exemplary operation of the delivery system shownin FIG. 5A.

FIG. 6A illustrates a phase-shifting interferometer feedback systemadapted to measures the surface shape of the cornea by comparing areference beam reflected from a reference minor and a signal beamreflected from the corneal surface.

FIG. 6B symbolically illustrates the operation of the holographicelement and the polarizing mask included in the interferometerconfiguration shown in FIG. 6A.

FIG. 6C provides an exemplary interference pattern (i.e.,interferogram), which is the intensity pattern detected by the CCDdetector.

FIG. 6D provides an alternative configuration of an interferometer forperforming profilometry of the corneal surface and providing feedback.

FIG. 6E provides a symbolic representation of aspects of the pixelatedpolarizing mask in the interferometer shown in FIG. 6D.

FIG. 7A illustrates the increase in Young's modulus with age and isassociated with cross-linking.

FIG. 7B provides an approach for calculating birefringence using acorneal polarimetry system.

FIG. 7C provides an alternative configuration of a corneal polarimetrysystem useful for detecting information indicative of the cornealbirefringence.

FIG. 7D provides another alternative configuration of a cornealpolarimetry system useful for detecting information indicative of thecorneal birefringence.

FIG. 7E schematically illustrates yet another configuration of a cornealpolarimetry system useful in extracting birefringence information of thecorneal tissue.

FIG. 8A illustrates a configuration utilizing multiple slit lamps toperform corneal topography and pachymetry.

FIG. 8B schematically illustrates an image of the cornea detected by thecamera in a configuration utilizing four slit lamps.

FIG. 8C illustrates an exemplary configuration of the bite plate forstabilizing a patient's eye during treatment and evaluation.

FIG. 9A provides a flowchart for activating the cross-linking agent in astaged procedure according to an aspect of the present disclosure.

FIG. 9B provides a flowchart for using an interferometer to conductpre-operative and post-operative examination of the corneal structure tobe treated with LASIK surgery and the cross-linking agent.

FIG. 9C provides an example embodiment for activating cross-linkingwhile controlling the concentration of the cross-linking agent, thepower of the initiating element, and the time delay between applicationand activation.

FIG. 9D provides an example embodiment for iteratively activatingcross-linking and varying the power and time delay between incrementalactivations with the initiating element.

FIG. 9E provides an example embodiment for iteratively activatingcross-linking similar to FIG. 9D, but where the cross-linking agent canbe applied repeatedly and at different concentrations.

FIG. 9F provides an embodiment similar to the embodiment of FIG. 9C, butwhere the diffusion of the cross-linking agent is assisted by use of aneutral compound after the cross-linking agent has been applied.

FIG. 9G provides an example embodiment similar to the embodiment shownin FIG. 9C, and where the bandwidth of the initiating element is alsocontrolled.

FIG. 10A illustrates a system having a mask positioned over the cornealsurface to control the application of the initiating element.

FIG. 10B illustrates an example pattern for the mask.

FIG. 11A illustrates a system having an optical element positionedbetween the light source and the eye for applying light to an eyeaccording to a desired pattern.

FIG. 11B illustrates an example desired pattern for applying theinitiating element to the eye.

FIG. 12A illustrates an example approach for stabilizing changes incorneal structure after LASIK treatment.

FIG. 12B illustrates another example approach for stabilizing changes incorneal structure after LASIK treatment.

FIG. 13 illustrates an example system for stabilizing changes in cornealstructure after eye treatment.

DETAILED DESCRIPTION

FIG. 1 provides a block diagram of an example delivery system 100 fordelivering a cross-linking agent 130 and an activator to a cornea 2 ofan eye 1 in order to initiate molecular cross-linking of cornealcollagen within the cornea 2. Cross-linking can stabilize corneal tissueand improve its biomechanical strength. The delivery system 100 includesan applicator 132 for applying the cross-linking agent 130 to the cornea2. The delivery system 100 includes a light source 110 and opticalelements 112 for directing light to the cornea 2. The delivery system100 also includes a controller 120 that is coupled to the applicator 132and the optical elements 112. The applicator 132 may be an apparatusadapted to apply the cross-linking agent 130 according to particularpatterns on the cornea 2 advantageous for causing cross-linking to takeplace within the corneal tissues. The applicator 132 may apply thecross-linking agent 130 to a corneal surface 2A (e.g., an epithelium),or to other locations on the eye 1. Particularly, the applicator 132 mayapply the cross-linking agent 130 to an abrasion or cut of the cornealsurface 2A to facilitate the transport or penetration of thecross-linking agent through the cornea 2 to a mid-depth region 2B.

As described below in connection with FIGS. 2A-2B, which describe anexemplary operation of the delivery system 100, the cross-linking agent130 is applied to the cornea 2 using the applicator 132. Once thecross-linking agent 130 has been applied to the cornea 2, thecross-linking agent 130 is initiated by the light source 110 (i.e. theinitiating element) to cause cross-linking agent 130 to absorb enoughenergy to release free oxygen radicals within the cornea 2. Oncereleased, the free oxygen radicals (i.e. singlet oxygen) form covalentbonds between corneal collagen fibrils and thereby cause the cornealcollagen fibrils to cross-link and change the structure of the cornea 2.For example, activation of the cross-linking agent 130 with the lightsource 110 delivered to the cornea 2 through the optical elements 112may result in cross-linking in the mid-depth region 2B of the cornea 2and thereby strengthen and stiffen the structure of the cornea 2.

Although eye therapy treatments may initially achieve desired reshapingof the cornea 2, the desired effects of reshaping the cornea 2 may bemitigated or reversed at least partially if the collagen fibrils withinthe cornea 2 continue to change after the desired reshaping has beenachieved. Indeed, complications may result from further changes to thecornea 2 after treatment. For example, a complication known aspost-LASIK ectasia may occur due to the permanent thinning and weakeningof the cornea 2 caused by LASIK surgery. In post-LASIK ectasia, thecornea 2 experiences progressive steepening (bulging).

Aspects of the present disclosure provide approaches for initiatingmolecular cross-linking of corneal collagen to stabilize corneal tissueand improve its biomechanical strength. For example, embodiments mayprovide devices and approaches for preserving the desired cornealstructure and shape that result from an eye therapy treatment, such asLASIK surgery or thermokeratoplasty. In addition, aspects of the presentdisclosure may provide devices and approaches for monitoring the shape,molecular cross-linking, and biomechanical strength of the cornealtissue and providing feedback to a system for providing iterativeinitiations of cross-linking of the corneal collagen. As describedherein, the devices and approaches disclosed herein may be used topreserve desired shape or structural changes following an eye therapytreatment by stabilizing the corneal tissue of the cornea 2. The devicesand approaches disclosed herein may also be used to enhance the strengthor biomechanical structural integrity of the corneal tissue apart fromany eye therapy treatment.

Therefore, aspects of the present disclosure provide devices andapproaches for preserving the desired corneal structure and shape thatresult from an eye treatment, such as LASIK surgery orthermokeratoplasty. In particular, embodiments may provide approachesfor initiating molecular cross-linking of the corneal collagen tostabilize the corneal tissue and improve its biomechanical strength andstiffness after the desired shape change has been achieved. In addition,embodiments may provide devices and approaches for monitoringcross-linking in the corneal collagen and the resulting changes inbiomechanical strength to provide a feedback to a system for inducingcross-linking in corneal tissue.

Some approaches initiate molecular cross-linking in a treatment zone ofthe cornea 2 where structural changes have been induced by, for example,LASIK surgery or thermokeratoplasty. However, it has been discoveredthat initiating cross-linking directly in this treatment zone may resultin undesired haze formation. Accordingly, aspects of the presentdisclosure also provide alternative techniques for initiatingcross-linking to minimize haze formation. In particular, the structuralchanges in the cornea 2 are stabilized by initiating cross-linking inselected areas of corneal collagen outside of the treatment zone. Thiscross-linking strengthens corneal tissue neighboring the treatment zoneto support and stabilize the actual structural changes within thetreatment zone.

With reference to FIG. 1, the optical elements 112 may include one ormore mirrors or lenses for directing and focusing the light emitted bythe light source 110 to a particular pattern on the cornea 2 suitablefor activating the cross-linking agent 130. The light source 110 may bean ultraviolet light source, and the light directed to the cornea 2through the optical elements 112 may be an activator of thecross-linking agent 130. The light source 110 may also alternatively oradditionally emit photons with greater or lesser energy levels thanultraviolet light photons. The delivery system 100 also includes acontroller 120 for controlling the operation of the optical elements 112or the applicator 132, or both. By controlling aspects of the operationof the optical elements 112 and the applicator 132, the controller 120can control the regions of the cornea 2 that receive the cross-linkingagent 130 and that are exposed to the light source 110. By controllingthe regions of the cornea 2 that receive the cross-linking agent 130 andthe light source 110, the controller 120 can control the particularregions of the cornea 2 that are strengthened and stabilized throughcross-linking of the corneal collagen fibrils. In an implementation, thecross-linking agent 130 can be applied generally to the eye 1, withoutregard to a particular region of the cornea 2 requiring strengthening,but the light source 110 can be directed to a particular region of thecornea 2 requiring strengthening, and thereby control the region of thecornea 2 wherein cross-linking is initiated by controlling the regionsof the cornea 2 that are exposed to the light source 110.

The optical elements 112 can be used to focus the light emitted by thelight source 110 to a particular focal plane within the cornea 2, suchas a focal plane that includes the mid-depth region 2B. In addition,according to particular embodiments, the optical elements 112 mayinclude one or more beam splitters for dividing a beam of light emittedby the light source 110, and may include one or more heat sinks forabsorbing light emitted by the light source 110. The optical elements112 may further include filters for partially blocking wavelengths oflight emitted by the light source 110 and for advantageously selectingparticular wavelengths of light to be directed to the cornea 2 foractivating the cross-linking agent 130. The controller 120 can also beadapted to control the light source 110 by, for example, toggling apower switch of the light source 110.

In an implementation, the controller 120 may include hardware and/orsoftware elements, and may be a computer. The controller 120 may includea processor, a memory storage, a microcontroller, digital logicelements, software running on a computer processor, or any combinationthereof. In an alternative implementation of the delivery system 100shown in FIG. 1, the controller 120 may be replaced by two or moreseparate controllers or processors. For example, one controller may beused to control the operation of the applicator 132, and thereby controlthe precise rate and location of the application of the cross-linkingagent 130 to the cornea 2. Another controller may be used to control theoperation of the optical elements 112, and thereby control withprecision the delivery of the light source 110 (i.e. the initiatingelement) to the cornea 2 by controlling any combination of: wavelength,bandwidth, intensity, power, location, depth of penetration, andduration of treatment. In addition, the function of the controller 120can be partially or wholly replaced by a manual operation. For example,the applicator 132 can be manually operated to deliver the cross-linkingagent 130 to the cornea 2 without the assistance of the controller 120.In addition, the controller 120 can operate the applicator 132 and theoptical elements 112 according to inputs dynamically supplied by anoperator of the delivery system 100 in real time, or can operateaccording to a pre-programmed sequence or routine.

Referring to FIG. 2A, an example embodiment 200A according to aspects ofthe present disclosure is illustrated. Specifically, in step 210, thecorneal tissue is treated with the cross-linking agent 130. Step 210 mayoccur, for example, after a treatment is applied to generate structuralchanges in the cornea and produce a desired shape change. Alternatively,step 210 may occur, for example, after it has been determined that thecorneal tissue requires stabilization or strengthening. Thecross-linking agent 130 is then activated in step 220 with an initiatingelement 222. In an example configuration, the initiating element 222 maybe the light source 110 shown in FIG. 1. Activation of the cross-linkingagent 130, for example, may be triggered thermally by the application ofmicrowaves or light.

As the example embodiment 200B of FIG. 2B shows further, Riboflavin maybe applied topically as a cross-linking agent 214 to the corneal tissuein step 210. As also shown in FIG. 2B, ultraviolet (UV) light may beapplied as an initiating element 224 in step 220 to initiatecross-linking in the corneal areas treated with Riboflavin.Specifically, the UV light initiates cross-linking activity by causingthe applied Riboflavin to release reactive oxygen radicals in thecorneal tissue. In particular, the Riboflavin acts as a sensitizer toconvert O₂ into singlet oxygen which causes cross-linking within thecorneal tissue.

According to one approach, the Riboflavin may be applied topically tothe corneal surface, and transepithelial delivery allows the Riboflavinto be applied to the corneal stroma. In general, the application of thecross-linking agent sufficiently introduces Riboflavin to mid-depthregions of the corneal tissue where stronger and more stable structureis desired.

Where the initiating element is UV light, the UV light may be generallyapplied to the corneal surface 2A (e.g. the epithelium) of the cornea 2to activate cross-linking. However, regions of the cornea 2 requiringstabilization may extend from the corneal surface 2A to a mid-depthregion 2B in the corneal stroma 2C. Generally applying UV light to thecorneal surface 2A may not allow sufficient penetration of the UV lightto activate necessary cross-linking at a mid-depth region of the cornea.Accordingly, embodiments according to aspects of the present disclosureprovide a delivery system that accurately and precisely delivers UVlight to the mid-depth region 2B where stronger and more stable cornealstructure is required. In particular, treatment may generate desiredchanges in corneal structure at the mid-depth region 2B.

FIG. 3 provides an example delivery system adapted as a laser scanningdevice 300 for delivering light to the cornea 2 employing laser scanningtechnology. The laser scanning device 300 has the light source 110 fordelivering a laser beam through an objective lens 346 into a small focalvolume within the cornea 2. The laser scanning device 300 also includesthe controller 120 for controlling the intensity profile of the lightdelivered to the cornea 2 using a minor array 344 and for controllingthe focal plane of the objective lens 346. The light source 110 can bean ultraviolet (UV) light source that emits a UV laser. A beam of light341 is emitted from the light source 110 (e.g., UV laser) and passes tothe mirror array 344. Within the minor array 344, the beam of light 341from the light source 110 is scanned over multiple mirrors adapted in anarray. The beam of light 341 can be scanned over the minors in the minorarray 344 using, for example, one or more adjustable mirrors to directthe beam of light 341 to point at each mirror in turn. The beam of light341 can be scanned over each minor one at a time. Alternately, the beamof light 341 can be split into one or more additional beams of lightusing, for example, a beam splitter, and the resultant multiple beams oflight can then be simultaneously scanned over multiple minors in themirror array 344.

By rapidly scanning the beam of light 341 over the mirrors in the mirrorarray 344, the minor array 344 outputs a light pattern 345, which has atwo dimensional intensity pattern. The two dimensional intensity patternof the light pattern 345 is generated by the minor array 344 accordingto, for example, the length of time that the beam of light 341 isscanned over each minor in the minor array 344. In particular, the lightpattern 345 can be considered a pixilated intensity pattern with eachpixel represented by a minor in the minor array 344 and the intensity ofthe light in each pixel of the light pattern 345 proportionate to thelength of time the beam of light 341 scans over the minor in the mirrorarray 344 corresponding to each pixel. In an implementation where thebeam of light 341 scans over each mirror in the minor array 344 in turnto create the light pattern 345, the light pattern 345 is properlyconsidered a time-averaged light pattern, as the output of the lightpattern 345 at any one particular instant in time may constitute lightfrom as few as a single pixel in the pixelated light pattern 345. In animplementation, the laser scanning technology of the delivery system 300may be similar to the technology utilized by Digital Light Processing™(DLP®) display technologies.

The mirror array 344 can include an array of small oscillating mirrors,controlled by minor position motors 347. The mirror position motors 347can be servo motors for causing the minors in the minor array 344 torotate so as to alternately reflect the beam of light 341 from the lightsource 340 toward the cornea 2. The controller 120 can control the lightpattern 345 generated in the minor array 344 using the mirror positionmotors 347. In addition, the controller 120 can control the depth withinthe cornea 2 that the light pattern 345 is focused to by controlling thelocation of the focal depth of the objective lens 346 relative to thecorneal surface 2A. The controller can utilize an objective lensposition motor 348 to raise and/or lower the objective lens 346 in orderto adjust the focal plane 6 of the light pattern 345 emitted from theminor array 344. By adjusting the focal plane 6 of the light pattern 345using the objective lens motor 348, and controlling the two-dimensionalintensity profile of the light pattern 345 using the minor positionmotors 347, the controller 120 is adapted to control the delivery of thelight source 110 to the cornea 2 in three dimensions. Thethree-dimensional pattern is generated by delivering the UV light toselected regions 5 on successive planes (parallel to the focal plane 6),which extend from the corneal surface 2A to the mid-depth region 2Bwithin the corneal stroma. The cross-linking agent 130 introduced intothe selected regions 5 is then activated as described above.

By scanning over selected regions 5 of a plane 6 at a particular depthwithin the cornea 2, the controller 120 can control the activation ofthe cross-linking agent 130 within the cornea 2 according to a threedimensional profile. In particular, the controller 120 can utilize thelaser scanning technology of the laser scanning device 300 to strengthenand stiffen the corneal tissues by activating cross-linking in athree-dimensional pattern within the cornea 2. In an implementation, theobjective lens 346 can be replaced by an optical train consisting ofmirrors and/or lenses to properly focus the light pattern 345 emittedfrom the mirror array 344. Additionally, the objective lens motor 348can be replaced by a motorized device for adjusting the position of theeye 1 relative to the objective lens 346, which can be fixed in space.For example, a chair or lift that makes fine motor step adjustments andadapted to hold a patient during eye treatment can be utilized to adjustthe position of the eye 1 relative to the objective lens 346.

Advantageously, the use of laser scanning technologies allowscross-linking to be activated beyond the corneal surface 2A of thecornea 2, at depths where stronger and more stable corneal structure isdesired, for example, where structural changes have been generated by aneye therapy treatment. In other words, the application of the initiatingelement (i.e., the light source 110) is applied precisely according to aselected three-dimensional pattern and is not limited to atwo-dimensional area at the corneal surface 2A of the cornea 2.

Although the embodiments described herein may initiate cross-linking inthe cornea according to an annular pattern defined, for example, by athermokeratoplasty applicator, the initiation pattern in otherembodiments is not limited to a particular shape. Indeed, energy may beapplied to the cornea in non-annular patterns, so cross-linking may beinitiated in areas of the cornea that correspond to the resultingnon-annular changes in corneal structure. Examples of the non-annularshapes by which energy may be applied to the cornea are described inU.S. patent Ser. No. 12/113,672, filed on May 1, 2008, the contents ofwhich are entirely incorporated herein by reference.

Some embodiments may employ Digital Micromirror Device (DMD) technologyto modulate the application of initiating light, e.g., UV light,spatially as well as a temporally. Using DMD technology, a controlledlight source projects the initiating light in a precise spatial patternthat is created by microscopically small mirrors laid out in a matrix ona semiconductor chip, known as a (DMD). Each minor represents one ormore pixels in the pattern of projected light. The power and duration atwhich the light is projected is determined as described elsewhere.

Embodiments may also employ aspects of multiphoton excitationmicroscopy. In particular, rather than delivering a single photon of aparticular wavelength to the cornea 2, the delivery system (e.g., 100 inFIG. 1) delivers multiple photons of longer wavelengths, i.e., lowerenergy, that combine to initiate the cross-linking. Advantageously,longer wavelengths are scattered within the cornea 2 to a lesser degreethan shorter wavelengths, which allows longer wavelengths of light topenetrate the cornea 2 more efficiently than shorter wavelength light.For example, in some embodiments, two photons may be employed, whereeach photon carries approximately half the energy necessary to excitethe molecules in the cross-linking agent 130 that release oxygenradicals. When a cross-linking agent molecule simultaneously absorbsboth photons, it absorbs enough energy to release reactive oxygenradicals in the corneal tissue. Embodiments may also utilize lowerenergy photons such that a cross-linking agent molecule mustsimultaneously absorb, for example, three, four, or five, photons torelease a reactive oxygen radical. The probability of thenear-simultaneous absorption of multiple photons is low, so a high fluxof excitation photons may be required, and the high flux may bedelivered through a femtosecond laser. Because multiple photons areabsorbed for activation of the cross-linking agent molecule, theprobability for activation increases with intensity. Therefore, moreactivation occurs where the delivery of light from the light source 110is tightly focused compared to where it is more diffuse. The lightsource 110 may deliver a laser beam to the cornea 2. Effectively,activation of the cross-linking agent 330 is restricted to the smallerfocal volume where the light source 310 is delivered to the cornea 2with a high flux. This localization advantageously allows for moreprecise control over where cross-linking is activated within the cornea2.

Referring again to FIG. 1, embodiments employing multiphoton excitationmicroscopy can also optionally employ multiple beams of lightsimultaneously applied to the cornea 2 by the light source 110. Forexample, a first and a second beam of light can each be directed fromthe optical elements 112 to an overlapping region of the cornea 2. Theregion of intersection of the two beams of light can be a volume in thecornea 2 where cross-linking is desired to occur. Multiple beams oflight can be delivered to the cornea 2 using aspects of the opticalelements 112 to split a beam of light emitted from the light source 310and direct the resulting multiple beams of light to an overlappingregion of the cornea 2. In addition, embodiments employing multiphotonexcitation microscopy can employ multiple light sources, each emitting abeam of light that is directed to the cornea 2, such that the multipleresulting beams of light overlap or intersect in a volume of the cornea2 where cross-linking is desired to occur. The region of intersectionmay be, for example, in the mid-depth region 2B of the cornea 2, and maybe below the corneal surface 2A. Aspects of the present disclosureemploying overlapping beams of light to achieve multi-photon microscopymay provide an additional approach to controlling the activation of thecross-linking agent 130 according to a three-dimensional profile withinthe cornea 2.

Aspects of the present disclosure, e.g., adjusting the parameters fordelivery and activation of the cross-linking agent, can be employed toreduce the amount of time required to achieve the desired cross-linking.In an example implementation, the time can be reduced from minutes toseconds. While some configurations may apply the initiating element(i.e., the light source 110) at a flux dose of 5 J/cm², aspects of thepresent disclosure allow larger doses of the initiating element, e.g.,multiples of 5 J/cm², to be applied to reduce the time required toachieve the desired cross-linking. Highly accelerated cross-linking isparticularly possible when using laser scanning technologies (such as inthe delivery system 300 provided in FIG. 3) in combination with afeedback system 400 as shown in FIG. 4, such as a rapid videoeye-tracking system, described below.

To decrease the treatment time, and advantageously generate strongercross-linking within the cornea 2, the initiating element (e.g., thelight source 110 shown in FIG. 1) may be applied with a power between 30mW and 1 W. The total dose of energy absorbed in the cornea 2 can bedescribed as an effective dose, which is an amount of energy absorbedthrough a region of the corneal surface 2A. For example the effectivedose for a region of the cornea 2 can be, for example, 5 J/cm², or ashigh as 20 J/cm² or 30 J/cm². The effective dose delivering the energyflux just described can be delivered from a single application ofenergy, or from repeated applications of energy. In an exampleimplementation where repeated applications of energy are employed todeliver an effective dose to a region of the cornea 2, each subsequentapplication of energy can be identical, or can be different according toinformation provided by the feedback system 400.

Treatment of the cornea 2 by activating cross-linking producesstructural changes to the corneal stroma. In general, the optomechanicalproperties of the cornea changes under stress. Such changes include:straightening out the waviness of the collagen fibrils; slippage androtation of individual lamellae; and breakdown of aggregated molecularsuperstructures into smaller units. In such cases, the application ofthe cross-linking agent 130 introduces sufficient amounts ofcross-linking agent to mid-depth regions 2B of the corneal tissue wherestronger and more stable structure is desired. The cross-linking agent130 may be applied directly to corneal tissue that have received an eyetherapy treatment and/or in areas around the treated tissue.

To enhance safety and efficacy of the application and the activation ofthe cross-linking agent, aspects of the present disclosure providetechniques for real time monitoring of the changes to the collagenfibrils with a feedback system 400 shown in FIG. 4. These techniques maybe employed to confirm whether appropriate doses of the cross-linkingagent 130 have been applied during treatment and/or to determine whetherthe cross-linking agent 130 has been sufficiently activated by theinitiating element (e.g., the light source 110). General studiesrelating to dosage may also apply these monitoring techniques.

Moreover, real time monitoring with the feedback system 400 may beemployed to identify when further application of the initiating element(e.g., the light source 110) yields no additional cross-linking. Wherethe initiating element is UV light, determining an end point for theapplication of the initiating element protects the corneal tissue fromunnecessary exposure to UV light. Accordingly, the safety of thecross-linking treatment is enhanced. The controller 120 for thecross-linking delivery system can automatically cease furtherapplication of UV light when the real time monitoring from the feedbacksystem 400 determines that no additional cross-linking is occurring.

FIG. 4 illustrates a delivery system incorporating the feedback system400. The feedback system 400 is adapted to gather measurements 402 fromthe eye 1, and pass feedback information 404 to the controller 120. Themeasurements 402 can be indicative of the progress of strengthening andstabilizing the corneal tissue. The measurements 402 can also provideposition information regarding the location of the eye and can detectmovement of the cornea 2, and particularly the regions of the cornealtissue requiring stabilization. The feedback information 404 is based onthe measurements 402 and provides input to the controller 120. Thecontroller 120 then analyzes the feedback information 404 to determinehow to adjust the application of the initiating element, e.g., the lightsource 110, and sends command signals 406 to the light source 110accordingly. Furthermore, the delivery system 100 shown in FIG. 1 can beadapted to incorporate the feedback system 100 and can adjust anycombination of the optical elements 112, the applicator 132, or thelight source 110 in order to control the activation of the cross-linkingagent 130 within the cornea 2 based on the feedback information 404received from the feedback system 400.

The feedback system 400 can be a video eye-tracking system as shown inFIG. 5A, which illustrates a delivery system 500 for activatingcross-linking in the cornea 2 with the laser scanning device 300. Thedelivery system 500 of FIG. 5A includes a video camera 510 for capturingdigital video image data 504 of the eye 1. The video camera 510generates the video image data 504 of the eye 1 in real time and tracksany movement of the eye 1. The video image data 504 generated by thevideo camera 510 is indicative of photons 502 reflected from the eye 1.The photons 502 can be reflected from the eye 1 from an ambient lightsource, or can be reflected from the eye 1 by a light source that isincorporated into the delivery system 500 adapted to direct light to theeye 1 for reflecting back to the video camera 510. Delivery systemsincluding the light source can optionally be adapted with the lightsource controlled by the controller 120. The delivery system 500 mayminimize movement of the eye 1 by minimizing movement of the head, suchas, for example, by use of a bite plate described below. However, theeye 1 can still move in the socket, relative to the head.

The real time video image data 504 (e.g., the series of images capturedby the video camera 510) are sent to the controller 120, which mayinclude processing hardware, such as a conventional personal computer orthe like. The controller 120 analyzes the data from the video camera 10,for example, according to programmed instructions on computer-readablestorage media, e.g., data storage hardware. In particular, thecontroller 120 identifies the image of the cornea 2 in the video imagedata 504 and determines the position of the cornea 2 relative to thedelivery system 500, and particularly relative to the laser scanningdevice 300. The controller 120 sends instructions 506 to the laserscanning device 300 to direct a pattern of UV light 508 to the positionof the cornea 2. For example, the instructions 506 can adjust opticalaspects of the laser scanning device 300 to center the pattern of UVlight 508 output from the laser scanning device 300 on the cornea 2. Thepattern of UV light 508 activates the cross-linking agent 130 in desiredareas and depths of corneal tissue according to aspects of the presentdisclosure described herein.

In addition, the video image data 504 can optionally include distanceinformation and the controller 130 can be adapted to further analyze thevideo image data 504 to determine the distance to the cornea 2 from thelaser scanning device 508 and can adjust the focal plane of the patternof UV light 508 directed to the cornea 2. For example, the distance tothe cornea 2 may be detected according to an auto-focus scheme thatautomatically determines the focal plane of the cornea 2, or may bedetermined according to an active ranging scheme, such as a laserranging or radar scheme. In an implementation, the video image data 504can be a series of images, and the controller 120 can be adapted toanalyze the images in the series of images individually or incombination to detect, for example, trends in the movement of the cornea2 in order to predict the location of the cornea 2 at a future time.

FIG. 5B illustrates an exemplary operation of the delivery system 500shown in FIG. 5A. In step 512, the video camera 510 captures the videoimage data 504 of the eye 1 based on the photons 502 reflected from theeye 1. In step 514, the video image data 504 is sent to the controller120. In step 516, the controller 120 sends the instructions 506 to thelaser scanning device 300 according to the detected position of thecornea 2. In step 518, the initiating element (e.g., UV light) isapplied to the cornea 2 according to the detected position of the cornea2. Following step 518, a decision is made whether to continue to gatherfeedback data using the video monitoring system. If feedback datacontinues to be desired, the exemplary operation returns to step 512 andrepeats until it is determined that feedback information is no longerrequired, at which point the exemplary operation ceases. In animplementation, the delivery system 500 can be adapted to operateaccording to the steps illustrated in FIG. 5B in real time, and canprovide position data about the location of the cornea 2 continuously,or in response to queries from, for example, the controller 120.

In general, the system 500 shown in FIG. 5A can correlate pixels of thevideo camera 510 with the pixels of the laser scanning device 300, sothe real time video image date 504 from the video camera 120 can beemployed to direct the pattern of UV light 508 from the laser scanningdevice 300 accurately to the desired corneal tissue even if there issome movement by the eye 1. The system 500 can be employed to map,associate, and/or correlate pixels in the video camera 510 with pixelsin the laser scanning device 300. Advantageously, the system 500 doesnot require mechanical tracking of the eye 1 and mechanical adjustment(of the laser scanning device 300) to apply the pattern of UV light 508accurately to the cornea 2.

In sum, implementations of aspects of the present disclosure stabilize athree-dimensional structure of corneal tissue through controlledapplication and activation of cross-linking in the corneal tissue. Forexample, the cross-linking agent 130 and/or the initiating element(e.g., the pattern of UV light 508) are applied in a series of timed andcontrolled steps to activate cross-linking incrementally. Moreover, thedelivery and activation of the cross-linking agent 130 at depths in thecornea 2 depend on the concentration(s) and diffusion times of thecross-linking agent 130 as well as the power(s) and bandwidths of theinitiating element. Furthermore, systems may employ laser scanningtechnologies in combination with a video eye-tracking system to achieveaccurate application of the initiating element 222 to the cornea 2.

Another technique for real time monitoring of the cornea 2 duringcross-linking treatment employs interferometry with a specializedphasecam interferometer (e.g., manufactured by 4dTechnology, Tucson,Ariz.). The interferometer takes up to 25 frames per second with a veryshort exposure so as to substantially minimize motion during an exposureduration. In an example, the exposure time can be less than onemillisecond. As the heart beats, the intraocular pressure (IOP) in theeye 1 increases and causes the corneal surface to extend outwardly by aslight amount. The deflection of the cornea 2 is determined bydeveloping a difference map between the peaks and valleys of the cardiacpulsate flow cycles. The deflection of the cornea provides an indicatorfor the strength of the corneal tissue. The deflection of the cornea 2may be used to measure changes in the biomechanical strength, rigidity,and/or stiffness during cross-linking treatment. Additionally,comparisons of an amount of deflection observed before and aftercross-linking treatment is applied to a cornea 2 may be used todetermine a change in biomechanical strength, rigidity, and/or stiffnessof the corneal tissue. In general, however, interferometry may beemployed to measure corneal strength before and after an eye surgery,before and after any eye treatment, or to monitor disease states. Thus,aspects of the present disclosure employ interferometry as a non-contacttechnique to determine the surface shape of the cornea 2 and develop adifference map to measure the deflection from IOP. The deflection of thecornea can then be used to determine changes in corneal strength duringcross-linking treatment.

To provide control over cross-linking activity, aspects of the presentdisclosure provide techniques for real time monitoring of the changes inthe strength of the corneal tissue. These techniques may be employed toconfirm whether appropriate doses of the cross-linking agent have beenapplied during treatment. Moreover, real time monitoring may be employedto identify when further application of the initiating element yields noadditional cross-linking. Where the initiating element is UV light,determining an end point for the application of the initiating elementprotects the corneal tissue from unnecessary exposure to UV light.Accordingly, the safety of the cross-linking treatment is enhanced. Thecontroller 120 for the cross-linking delivery system (e.g., the deliverysystem 100 in FIG. 1) can automatically cease further application of UVlight when the real time monitoring determines that no additionalcross-linking is occurring.

FIG. 6A illustrates a phase-shifting interferometer adapted to measurethe surface shape of the cornea 2 by comparing a reference beam 616(i.e., reference wavefront) reflected from a reference mirror 612 and asignal beam 614 (i.e., signal wavefront) reflected from the cornealsurface 2A. Interferometry involves the analysis of an interferencepattern created by the superposition of two or more waves. Theinterferometer illustrated in FIG. 6A is adapted as a Twyman-Greeninterferometer and is adapted to record the interference pattern, i.e.,interferogram, of the superposition of the reference beam 616 and thesignal beam 614 using a CCD detector 660 such as a camera. Although, theCCD detector 660 may be replaced by any photosensitive sensor suitablefor converting an optical intensity sensed at an array of pixellocations to an electrical charge or current. The interferometer shownin FIG. 6A includes a light source 610, a spreading lens 602, aconverging lens 604, an angled mirror 606, a polarizing beam splitter(PBS) 622, and a reference minor 612. The interferometer also includestwo quarter wave plates 608. The quarter-wave plates 608 can be created,at least in part, from a birefringent material that causes beams oflight passing through the quarter-wave plates 608 to rotate thepolarization of light of the beam of light. In particular, the quarterwave plate 608 can cause an incoming beam of light having a polarizationthat is a combination of two orthogonal components, to result in anoutgoing beam of light where one of the two orthogonal polarizationcomponents is phase-delayed relative to the other by one-quarterwavelength. In a configuration, the quarter-wave plates 608 can convertlinearly polarized light to circularly polarized light. Theinterferometer also has an optical transfer 630, which can include acombination of lenses, filters, and minors to focus, align, and direct asuperimposed beam 635 to a holographic element 640. The superimposedbeam 635 is a superposition of the signal beam 614 and the referencebeam 616. The holographic element 640 can split the superimposed beam635 into four copies for being applied to a polarizing quad filter 650.The output of the polarizing quad filter 650 is then recorded by the CCDdetector 660. The resulting image or intensity pattern captured by theCCD detector 660 is then sent to the controller 120 for analysis. Thecontroller 120 can also receive an input from a distance measurementsystem 670 adapted to monitor a distance between the eye 1 and aspectsof the interferometer. Additional optical elements may be included atvarious locations within the optical path of the interferometer tospread and/or focus the beams of light.

In an exemplary operation of the interferometer illustrated in FIG. 6A,a beam of light is emitted from the light source 610. The beam of lightis then spread and collimated with the lenses 602, 604 such as isappropriate for directing the beam toward the polarizing beam splitter622. The spread beam is then reflected on the mirror 606 and directedtoward the polarizing beam splitter 622. A half-wave plate or othersuitable birefringent material or polarizing filter may be inserted inthe optical path between the light source 610 and the polarizing beamsplitter (PBS) 622 to cause the beam of light directed to the PBS 622 tohave an appropriate polarization angle relative to the PBS to allow adesired amount of light having orthogonal polarizations to betransmitted and reflected by the PBS 622. For example, the polarizationof the incoming beam of light can be selected such that the PBS 622allows roughly equal amounts of light to be reflected and transmitted,with each having orthogonal linear polarization.

Upon reaching the PBS 622, the beam of light is divided according to thepolarization of the incoming beam of light, with roughly half directedtoward the eye 1 to be reflected by the corneal surface 2A of the cornea2. The other half, which may be orthogonally polarized relative to thebeam directed toward the eye 1, is directed toward the reference minor612. The light reflected from the corneal surface 2A is the signal beam614. The light reflected from the reference mirror 612 is the referencebeam 616. Each of the beams emitted from the PBS 622 is passed throughone of the quarter wave plates 608, which rotates the signal beam 614and the reference beam 616 after reflection while retaining their mutualorthogonal linear polarization states. The configuration of the PBS 622along with the quarter wave plates 608 allows the reference beam 616 andthe signal beam 614 to be transmitted through and reflected from the PBS622 toward the optical transfer 630 along a common optical path.Additional lenses may be used between the PBS 622 and the eye 1 orbetween the PBS 622 and the test mirror 612 in order to appropriatelyspread or narrow the beam of light to simultaneously illuminate theentire area of the eye 1 (or the reference minor 612) to be measured,and to return substantially collimated beams (e.g., the reference beam616 and the signal beam 614) back to the PBS 622.

The light source 610 may emit a linearly polarized beam of light, or mayemit a beam of light which is then filtered to pass a linearly polarizedbeam of light. The wavelength of the light emitted from the light source610 may be chosen to be suitable for the various optical components inthe interferometer and for the CCD detector 660. In addition, thewavelength of the light source 610 may be chosen to be a wavelength oflight that is safe for being reflected from the corneal surface 2A ofthe eye 1. Generally, the reference minor 616 can be any referencesurface suitable for reflecting light, and can optionally have a flatconfiguration or can have a curved configuration. In particular, thereference minor 616 may be shaped according to a desired shape of thecorneal surface 2A of the cornea 2, or may be shaped according to atypical shape of a corneal surface, and may be an aspheric surface. Inan example where the reference mirror 616 is shaped as an ideal ortypical corneal surface, the interference pattern displayed on theinterferogram reveals the differences between the signal beam 614 (i.e.,signal wavefront) reflected from the corneal surface 2A of the eye 1 andthe reference beam 616 (i.e., reference wavefront) reflected from theideal or typical or corneal surface. Implementations utilizing a curvedsurface as the reference surface can incorporate a converging lens todirect the beam to the reference surface. In an implementation where thereference surface is a convex surface, the converging lens is positionedsuch that the reference surface is closer to the converging lens thanthe focus of the converging lens; however, where the reference surfaceis a concave surface, the converging lens is positioned such that thereference surface is further from the converging lens than the focus ofthe converging lens.

The light directed toward the optical transfer 630 is a superposition ofthe reference beam 616 and the signal beam 614, which may beorthogonally polarized relative to one another. In particular, thereference beam 616 and the signal beam 614 can be orthogonallycircularly polarized relative to one another. The optical transfer 630may include a combination of lenses, minors, and apertures to relay thesuperimposed beam 635 onto the holographic element 640. The aperture(not separately shown), which can be incorporated in the opticaltransfer 630, can be chosen such that the diffraction-limited spot sizeat the CCD detector 660 is approximately 2 effective pixels in diameterin order to avoid aliasing of the interference pattern spatialfrequency. An appropriate selection of the aperture ensures that spatialfrequencies higher than the pixel spacing of the CCD detector 660 arenot present in the resulting interferograms measured by the CCD detector660.

FIG. 6B symbolically illustrates the operation of the holographicelement 640 and the polarizing quad filter 650 included in theinterferometer configuration shown in FIG. 6A. With reference to FIGS.6A and 6B, the superimposed beam 635, which is a superposition of thereference beam 616 and the signal beam 614 is directed toward theholographic element 640. The signal beam 614 is represented symbolicallyas having a wavefront delayed from the wavefront of the reference beam616 by varying amounts. The signal beam 614 is shown with a curved lineindicating exemplary amounts of delay relative to the reference beam 616across a profile of the signal beam 614. The amount of delay between thesignal beam 614 and the reference beam 616 corresponds to the differencein optical path length between the path taken by the reference beam 616and the signal beam 614, and therefore corresponds to differencesbetween the corneal surface 2A and the reference mirror 612.

FIG. 6C provides an exemplary interference pattern (i.e.,interferogram), which is the intensity pattern (i.e., image) detected bythe CCD detector 660 and output from the polarizing quad filter 650. Ina configuration, the difference in optical path length between thesignal beam 614 and the reference beam 616 may be revealed by theinterference pattern (i.e., interferogram) recorded by the CCD detector,and allows for performing profilometry (i.e., measuring the absolutethree-dimensional profile of a solid object) of the corneal surface 2Aof the eye 1. The holographic element 640 splits the superposition beam635 into four substantially identical copies and projects the fourcopies onto the polarizing quad filter 650. Additional optical elementsmay be employed to provide a collimated beam to the polarizing quadfilter 650. The polarizing quad filter 650 is divided into fourquadrants, with each quadrant introducing a different effectivephase-delay between the reference and test wavefronts at each pixel. Thephase mask may be constructed from a birefringent plate, or from fourseparate birefringent plates. Alternatively, the polarizing mask 640 maybe constructed from an array of four polarizers, with each having adifferent polarizing angle.

The intensity of two beams having orthogonal circular polarization(e.g., the reference beam 616 and the signal beam 614) interfered by apolarizer with angle α is given by Eq. 1.

$\begin{matrix}{{I\left( {x,y} \right)} = {\frac{1}{2}\left( {{Ir} + {Is} + {2\sqrt{{{Ir} \cdot {Is}}\; {\cos \left( {{{\Delta\theta}\left( {x,y} \right)} + {2\alpha}} \right)}}}} \right)}} & \left( {{Eq}.\mspace{14mu} 1} \right)\end{matrix}$

In Eq. 1, Ir and Is are the intensities of the reference beam 616 andthe signal beam 614, respectively and Δθ(x,y) is the phase shift betweenthe reference beam 616 and the signal beam 614 due to the optical pathdifference for each pixel array coordinate. In an implementation, bothIr and Is can vary with x and y. So, by constructing the polarizing quadfilter 650 with polarizers in each quadrant having angles of 0 degrees,45 degrees, 90 degrees, and 135 degrees, the following transferfunctions provide the intensity of light transmitted through eachquadrant of the polarizing quad filter 650.

$\begin{matrix}{{A\left( {x,y} \right)} = {\frac{1}{2}\left( {{Ir} + {Is} + {2\sqrt{{{Ir} \cdot {Is}}\; {\cos \left( {{\Delta\theta}\left( {x,y} \right)} \right)}}}} \right)}} & \left( {{{Eq}.\mspace{14mu} 2}\; a} \right) \\{{B\left( {x,y} \right)} = {\frac{1}{2}\left( {{Ir} + {Is} + {2\sqrt{{{Ir} \cdot {Is}}\; {\cos \left( {{{\Delta\theta}\left( {x,y} \right)} + \frac{\pi}{2}} \right)}}}} \right)}} & \left( {{{Eq}.\mspace{14mu} 2}\; b} \right) \\{{C\left( {x,y} \right)} = {\frac{1}{2}\left( {{Ir} + {Is} + {2\sqrt{{{Ir} \cdot {Is}}\; {\cos \left( {{{\Delta\theta}\left( {x,y} \right)} + \pi} \right)}}}} \right)}} & \left( {{{Eq}.\mspace{14mu} 2}\; c} \right) \\{{D\left( {x,y} \right)} = {\frac{1}{2}\left( {{Ir} + {Is} + {2\sqrt{{{Ir} \cdot {Is}}\; {\cos \left( {{{\Delta\theta}\left( {x,y} \right)} + \frac{3\pi}{2}} \right)}}}} \right)}} & \left( {{{Eq}.\mspace{14mu} 2}\; d} \right)\end{matrix}$

The transfer functions provided in Eqs. 2a through 2d provide theintensities measured at each pixel coordinate for the light transmittedthrough the polarizing quad filter 650. Eq. 2a may provide the intensityof light passing through the first quadrant of the polarizing quadfilter 650, which has a polarizing angle of 0 degrees relative to the x,y orientation of the pixel array. The first quadrant of the polarizingquad filter 650 therefore interferes in-phase components of the signalbeam 614 and the reference beam 616 present in the superimposed beam635. Eq. 2b may provide the intensity of light passing through thesecond quadrant of the polarizing quad filter 650, which has apolarizing angle of 45 degrees relative to the x, y orientation of thepixel array. The second quadrant of the polarizing quad filter 650therefore interferes in-phase quadrature components of the signal beam614 and the reference beam 616. Eq. 2c may provide the intensity oflight passing through the third quadrature of the polarizing quad filter650, which has a polarizing angle of 90 degrees relative to the x, yorientation of the pixel array. The third quadrant of the polarizingquad filter 650 therefore interferes out-of-phase components of thesignal beam 614 and the reference beam 616. Eq. 2d may provide theintensity of light passing through the fourth quadrature of thepolarizing quad filter 650, which has a polarizing angle of 135 degreesrelative to the x, y orientation of the pixel array. The fourth quadrantof the polarizing quad filter 650 therefore interferes out-of-phasequadrature components of the signal beam 614 and the reference beam 616.

Using the interference pattern detected by the CCD detector 660, methodscan be employed to calculate the phase difference and modulation indexto reveal the optical path difference between the reference beam 616 andthe signal beam 614, and thereby perform profilometry of the cornealsurface 2A of the eye 1. The transfer functions of Eqs 2a through 2d maybe used to compute the phase difference between the signal beam 614 andthe reference beam 616 at each x, y location according to a four-bucketalgorithm, e.g.:

$\begin{matrix}{{{\Delta\theta}\left( {x,y} \right)} = {\arctan \left( \frac{{C\left( {x,y} \right)} - {A\left( {x,y} \right)}}{{D\left( {x,y} \right)} - {B\left( {x,y} \right)}} \right)}} & \left( {{Eq}.\mspace{14mu} 3} \right)\end{matrix}$

Eqs. 2 and 3 provide an example algorithm for computing a phasedifference map for a single exposure of the CCD detector 660.Alternatively, the phase difference at each spatial coordinate can becomputed according to a windowed convolution algorithm. A windowedconvolution algorithm may provide less phase-dependent error, althoughthe spatial frequency is at least partially filtered by the convolutionprocess and may therefore have reduced spatial frequency. In addition,implementations utilizing a convolution algorithm to provide real timephase difference maps may require additional computational resources.

Alternatively, an interferometer may be employed with implementations ofthe present disclosure to perform profilometry of the eye 1 by gatheringthe four interference patterns without the holographic element andwithout simultaneously capturing the four interferograms with a singleexposure. Such an interferometer may utilize a configuration whichchanges the polarizing mask following each exposure of the CCD detector660 such that four subsequent exposures provide interference patternsfor each polarizing angle and allow for computing the phase differencemap according to Eqs. 2 and 3.

Systems implementing algorithms for computing a profile of the cornealsurface 2A of the eye 1 from the phase difference map may also take asan input a distance between the corneal surface 2A and theinterferometer (which can be provided, for example, by the distancemeasurement system 670). The distance monitored by the distancemeasurement system 670 can be used to determine a scaling of theintensity patterns captured by the CCD detector 660 and to determine aradius of curvature of the cornea 2, and thus the optical power of theeye 1. The distance measurement system 670 may be implemented by twocameras focusing on the cornea 2, but oriented at an angle relative toone another, and separated by a known distance, such that the anglebetween the orientations of the two cameras when both are focused on thecornea 2 provides an estimation of the distance according to standardtrigonometric analysis. The distance measurement system 670 may beimplemented as a high resolution camera capturing images from a knownposition. The high resolution camera may be oriented at approximately90° to the optical axis of the eye 1, such that the edge of the eye 1can be mapped to a pixel location of the high resolution camera, whichcorresponds to a distance from the interferometer. The distancemeasurement system 670 may be implemented as a separate interferometer,such as a Michelson interferometer. In addition, the distancemeasurement system 670 may be adapted as an active ranging techniquewhich uses reflected signals correlated with reference signals tomeasure time delays, such as a doppler, ultrasound, or optical rangingsystem. Additionally, the distance measurement system 670 may beimplemented by a configuration having multiple slit lamps, such as theconfiguration illustrated by FIG. 8A, which is described below infurther detail. As shown in FIG. 6A, the distance measurement system 670is adapted to provide an output indicative of the monitored distance tothe controller 120. The distance measurement system 670 can be a systemintegrated with the interferometer or can be implemented as a separatefrom the interferometer and is adapted to provide an input to thealgorithms for performing corneal topography. In some aspects, theoutput of the distance measurement system 670 may be considered amonitored distance, an estimated distance, or a measured distance, andmay be used interchangeably.

The above-described algorithms can be performed automatically by thecontroller 120 or by one or more separate computers adapted to receivethe intensity patterns captured by the CCD detector 660 and themonitored distance from the distance measurement system 670.

To be useful for performing profilometry of the cornea surface 2A, thefringes in the interference pattern (i.e., the interferograms) producedby the phase-shifting interferometer must be sufficiently stable in theimage plane to measure the surface shape of the cornea 2. Due tochanges, for example, in saccadic eye movement and eye fixation, thecorneal surface 2A changes periodically and may not remain sufficientlystable for conventional phase-shifting interferometers. As such, thephase-shifting interferometer in the present embodiments shortens thedata acquisition time to reduce the amount of relative motion andeffectively freeze the fringe image (i.e., the interferograms) duringmeasurement.

In particular, rapid data acquisition can be achieved by dynamicinterferometry. Dynamic interferometry in the present implementationsuses polarization to generate the required phase shift and capturesmultiple fringe images on a single camera to acquire the data. Dynamicinterferometers can make single-frame phase measurements with shortexposures while capturing the phase changes. Moreover, signal averagingcan be advantageously employed with dynamic interferometry, e.g., toreduce systematic errors.

Advantageously, using the holographic element 640 allows for theinterference patterns corresponding to each of the four polarizingangles to be detected simultaneously with a single exposure of the CCDdetector 660. Simultaneous detection of the interferograms with a singleexposure of the CCD detector 660 offers significant immunity tovibration, which may occur between separate exposures. Simultaneousdetection also allows for capturing the profile of the corneal surface2A during an duration of time that does not exceed the duration of theexposure of the CCD detector 660. In an example, the duration of theexposure of the CCD detector 660 can be less than one millisecond andcan be as low as thirty microseconds.

FIG. 6D provides an alternative configuration of an interferometer forperforming profilometry of the corneal surface 2A. The interferometer inFIG. 6D is similar in some respects to the interferometer shown in FIG.6A, with the principal difference that the holographic element 640 andpolarizing quad filter 650 as shown in FIG. 6B are replaced with apixelated polarizing filter 652. The interferometer shown in FIG. 6Dalso includes cornea imaging optics 615 between the PBS 622 and the eye1 for spreading, diffusing, focusing, and/or collimating the lightdirected to and reflected from the eye 1. In particular, the corneaimaging optics 615 can include a lens or combination of lenses forcausing the beam from the PBS 622 to converges to meet the radius ofcurvature of the cornea 2, and then collimate the signal beam 614 afterit is reflected from the corneal surface 2A. The cornea imaging optics615 can also be employed in connection with the interferometerconfiguration illustrated in FIG. 6A.

Further illustrated in FIG. 6D are positioning motors 617 for adjustingthe corneal imaging optics 615. The positioning motors 617 may include asingle motor or multiple motors for manipulating a position of one ormore aspects of the corneal imaging optics 615 according to inputsignals from the controller 120. For example, the positioning motors 617may include a first and second motor for manipulating the position of aconvergent lens most proximate the cornea 2 according to input signalsfrom the controller 120. The positioning motors may be adapted to adjustthe position of the convergent lens in directions wholly or partiallyperpendicular to the orientation of the signal beam 614, or in adirection parallel to the orientation of the signal beam 614. Thepositioning motors may incorporate piezo electric crystals for makingfine adjustments. The controller 120 may be further adapted to adjustthe position of the corneal imaging optics 615 according to informationreceived by the camera 660.

For example, the controller 120 may be adapted to determine a centroidposition of the specular reflection of light emerging from the cornea 2.The centroid position may be determined by combining intensityinformation detected at adjacent pixels of the camera 660 in order toachieve an estimate of a centroid position with a greater precision thanan estimate of an individual pixel. In an implementation, the centroidposition may be determined at a rate of, for example 200 Hz, and theinput signals may be sent to the positioning motors 617 at the same rate(i.e., 200 Hz). Alternatively, the controller 120 may incorporate aseparate camera different from the camera 660 for measuring the centroidposition of the specular reflection. To provide the positioningfunction, the camera 660 (or the separate camera) need only have aresolution of, for example, 16 pixels by 16 pixels. A relatively lowresolution allows for processing of the image to determine the centroidposition to occur more rapidly. Once an energy distribution of receivedintensities is detected by the camera 660, the controller may be adaptedto operate the positioning motors 617 so as to maintain the initiallyobserved energy distribution. Maintenance of the energy distribution maybe achieved by manipulating the corneal imaging optics 615 in threedimensions.

Implementations tracking the position of the eye, and adjusting opticalelements according to a monitored (or tracked) position may be furtheradapted to distinguish a rotational movement of the eye 1 from atranslational displacement of the eye. A rotational movement of the eye1 may be determined by monitoring a fourth Pukinje image (Pukinje IV) ofthe eye with respect to an aspect of the eye which changes with rotationof the eye, such as, for example, the outer ring of the pupil of the eye1. The Pukinje IV image results from the specular reflection from theback surface of the lens of the eye 1. Monitoring the Pukinje IV imageallows for separately monitoring the rotational and translationalaspects of movements of the eye 1, because the Pukinje IV image does notchange much during a rotational movement of the eye. Separating therotational and translational movements of the eye can allow foradjusting optical aspects of the feedback system (or the applicationsystem) based on monitored translational movements, but not based onmonitored rotational movements.

Additionally, or alternatively, the tracked position of the eye can beused to adjust a position of the eye 1. Similar to the descriptionprovided in connection with FIGS. 7B and 7C, a bite plate (and/oranother head restraint device) may be provided that is coupled topositioning motors. Adjusting the positioning motors can move theposition of the patient's head, and thus the position of the patient'seye. Tracking the position of the eye 1 allows for aligning themonitoring system and/or the treatment system by moving the eye 1 (e.g.,via the bite plate 770 connected to positioning motors 772), by movingthe monitoring and/or treatment system (e.g., by adjusting a position ofan objective optical element), or any combination thereof.

FIG. 6E provides a symbolic representation of aspects of the pixelatedpolarizing filter 652 in the interferometer shown in FIG. 6D. Thepixelated polarizing filter 652 is in some respects similar to thepolarizing quad filter 650, but in miniature and repeated in an array.In principle, the pixelated polarizing filter 652 could be constructedfrom an etched birefringent plate, but such a device is difficult tomanufacture accurately. The pixelated polarizing filter 652 can beconstructed from an array of micropolarizers such that the number ofentries in the array of micropolarizers is similar to, or even identicalto, the number of pixels in the CCD detector 660. FIG. 6E symbolicallyrepresents a portion of the pixelated polarizing filter 652, which isshown as an array, with each set of four pixels forming a group oflinear micropolarizers. In an implementation, the pixelated polarizingfilter 652 may be referred to as a pixelated polarizing plate.

Generally, information for conducting profilometry of the eye 1 can beextracted from a configuration where the effective polarization of thepixelated polarizing plate 652 is spatially distributed. The effectivepolarization of the pixelated polarizing filter 652 can have a regularrepeating pattern, with out of phase polarizers alternating along thecolumns. For example, pixelated polarizers for interfering at 0 degrees(corresponding to the transfer function for A(x,y)) and 180 degrees (C.)can be arranged in an alternating pattern in one column, and pixelatedpolarizers for interfering at 90 degrees (B) and 270 degrees (D) can bearranged in an alternating pattern in adjacent columns. Alternating theout-of-phase signals advantageously minimizes the amount ofphase-dependent error due to smearing of the sensing array in the CCDdetector 660, which can be particularly prone to smearing effects forshort exposure times. The four interferograms can then be analyzed tocompute phase difference map(s) associated with the surface(s) beingmonitored and determine surface profile(s) for the surface(s). The fourinterferograms can be intensity patterns captured by the CCD detector660, each associated with a polarization state (e.g., 0°, 90°, 180°,270°).

The pixelated polarizing filter 652 is illustrated as being positionedadjacent to the CCD detector 660, however the pixelated polarizingfilter 652 can alternatively be positioned at the focal plane of theoptical transfer 630 and additional relay optics can be used to conveythe light transmitted through the pixelated polarizing filter 652 to theCCD detector 660. In particular, in an implementation where the size ofthe pixels in the pixelated polarizing filter 652 are larger than thepixels of the CCD detector 660, optical elements may be employed toscale the effective pixel size of the CCD detector 660 as desiredrelative to the pixelated polarizing filter 652 by introducingmagnifying optical elements. Thus, the physical spacing of the pixelatedpolarizing filter 652 and the sensor array of the CCD detector 660 donot need to be equal.

The interferograms pictured in FIG. 6E can be created from the output ofthe pixelated polarizing filter 652 by combining every fourth pixel inthe CCD detector 660 to create the four interferogram patterns. Similarto the configuration of the interferometer shown in FIG. 6A, thepixelated polarizing filter 652 allows for the four interferograms to becaptured simultaneously with a single exposure of the CCD detector 660.In an example, the duration of the exposure of the CCD detector 660 canbe less than one millisecond and can be as low as thirty microseconds.

While phase-shifting interferometers have been shown employingpolarizing beam splitters and polarizing masks to compare the phasedifferences between the reference beam 616 and the signal beam 614 inFIGS. 6A through 6E, generally any interferometer for comparing thephase shift between a reference beam reflected from a known referencesurface and a signal beam reflected from a surface of the eye 1 can beemployed to perform profilometry of the eye 1.

One technique for determining the three-dimensional surface shape of theeye 1, and particularly the cornea 2, employs an analysis of the phasedifference map. The phase difference map can be created, for example,using the interferograms and Eqs. 2 and 3. The surface shape of the eye1 relative to the reference minor 612 can be extracted from the phasedifference map. The phase difference map may be a table which providesthe phase difference between the reference beam 616 and the signal beam614 for each effective pixel position of the four interferograms. Aswill be appreciated, the phase difference map includes ambiguitiesaccording to the modulo 2π behavior of the arctangent function in Eq. 3.This ambiguity can be resolved by the process of spatial phaseunwrapping. For example, the difference in the optical path length ofthe reference beam 616 and the signal beam 614 between two pixels in thephase difference map that both have the same phase, can be a distanceequal to an integer number of wavelengths of the light emitted by thelight source 610. Analyzing the phase difference map in the context ofsurrounding entries allows for “unwrapping” the phase ambiguity.Generally such analysis can be performed by a computer or data analysissystem adapted to automatically analyze the measurements from the CCDdetector 660 according to a pre-programmed routine. Similar to thedescription provided above in connection with FIG. 6A, the profile ofthe corneal surface 2A may be estimated based on the phase differencemap and an estimated distance from the corneal surface 2A to theinterferometer, which may be supplied by the distance measurement system670. The analysis of the measurements to estimate the profile of thecorneal surface 2A may be performed by the controller 120.

Once the surface shape of the eye 1 has been measured during a firstexposure, subsequent surface shapes of the eye 1 measured duringsubsequent exposures can be compared with the first measured surfaceshape in order to determine changes in the surface shape (e.g., adynamic deformation of the corneal surface), and thereby determine thebiomechanical corneal strength or stiffness. Generally, such an analysiscan be performed for a data array of 1 million pixels at a rate ofseveral frames per second using a 2 GHz Pentium computer. In an example,an estimation of dynamic deformation of the corneal surface is estimatedbased on a series of subsequently captured surface profiles. Generally,however, where the corneal surface 2A is experiencing an approximatelyperiodic perturbation (such as perturbations due to changes in IOP,which are rhythmically associated with a subject's heartbeat), anestimation of dynamic deformation is advantageously based on samplesfrom the full phase-space of the perturbation. Systems may incorporatesynchronizing devices to associate corneal surface profile measurementswith an indication of a phase of the subject's heartbeat. The phase ofthe subject's heartbeat may be indicated by a separate cardiacmeasurement device, or may be extracted from the series of measurementsby a signal processing technique adapted to effectively wrap or foldmeasurements on top of one another according to their associated phaseand then optimizing the associated phases to minimize noise in the phasespace modulation. Systems relying on perturbations other than IOP (or inaddition to IOP) may similarly incorporate sensors to synchronizecorneal surface profile estimations with an associated phase of thesource of the perturbation.

After initial alignment, camera recording may be automatically initiatedby monitoring the blink response of the patient. Furthermore, theembodiments can be adapted to monitor the blink response of the eye 1and to report characteristics of the blink response, such as the blinkrate, the blink duration, and characteristics of tear film build-up andbreak-up associated with the blink response. In addition, embodimentsmay be adapted to report average, minimum, maximum, and median blinkrates and blink durations over a period of time.

Aspects may further provide for estimating tear film volume based on adifference between measured profiles of the corneal surface 2A. In anexample, the tear film volume estimation can be based on a differencebetween subsequently measured profiles off the corneal surface.

In general, embodiments according to the present disclosure may provideintegrated systems that evaluate additional characteristics of the eye 1in addition to using an interferometer to measure the corneal surface 2Aand strength of the corneal tissue. Embodiments may provide analyses ofany combination of topography, wavefront, autorefraction, keratometry,pupillometry, tear film measurement, etc. Indeed, as explained withreference to FIG. 9B, the pre-operative and post-operative examinationsin steps 916 and 918, respectively, may include determining visualacuity, refractive error, pupil size, intraocular pressure (IOP),corneal thickness, corneal topography, wavefront analysis, presence ofdry eye-related disorders, etc. Aspects of the examination may beconducted at least in part with configurations of the presentdisclosure.

For example, the interferometry techniques described above in connectionwith FIGS. 6A through 6E may be employed to measure tear film thicknessand evaluate tear film stability. Problems relating to tear filmbreak-up and dry eye can be diagnosed. Indeed, such evaluation enables apractitioner to determine during a pre-operative examination whether apatient is a candidate for refractive surgery, such as LASIK (see step912 of FIG. 9B). Tear film measurement can be enhanced with artificialtears containing microbeads of specific sizes and concentrations. Theartificial tears can optionally have fluorescent markers to assist inmeasuring tear fluid dynamics by a measurement apparatus sensitive tofluorescence.

As described previously, an interferometer can provide data on thestrength of the cornea 2 by measuring deflections of the corneal surfacecaused cardiac pulsate flow cycles. In general, changes in diastolic andsystolic pressure magnitudes and differences may be analyzed with datafrom the interferometer to determine IOP and other biomechanicalcharacteristics of the cornea 2.

Rather than relying on cardiac activity, however, the interferometer inother implementations can provide data on the corneal structure bymeasuring the response of the cornea 2 to a deformation that is appliedfrom a controlled external source. For example, an ultrasonic pulse maybe applied to the eye 1. Alternatively or additionally, pulses sweepingthrough a range of frequencies may be applied to the eye 1 and theinterferometer can look for resonances that indicate the structuralproperties of the cornea tissue. In other examples, the external sourceis positioned so that it is not in direct contact with the eye, and apuff of air or the like may be delivered to cause deformation of thecornea 2 in a controlled manner.

In another embodiment of the light source 610 in the interferometrysystem may be a multispectral light source. In an implementation, movinga reference arm of the interferometer, which can adjust a position ofthe reference surface 612, allows for probing the different surfaceswithin the eye. For example, the different surfaces within the eye canbe probed by looking at the different spectral oscillations off of eachrefractive surface interface (e.g., the interfaces between the layersassociated with the eye 1). The spectral oscillations can be theconstructive and deconstructive interference between the layers atdifferent wavelengths. In this manner, the surface layer shape as wellas layer thickness can be measured. The surfaces and layers that can bemeasured include, without limitation: the tear film layers, theendothelium, Bowman's membrane, stroma, Descemet's membrane, and theendothelium. The surfaces that can be measured include the surfacesdefined by the interfaces between each of the refractive layers (e.g.,the tear film layers, the endothelium, Bowman's membrane, stroma,Descemet's membrane, and the endothelium). In addition, layers (andassociated surfaces defined by interfaces between the layers) mayinclude, for example, a contact lens and its tear film above and betweenthe contact lens and the epithelium. Implementations may also measureposterior and anterior surfaces of the lens of the eye.

Further embodiments of the present disclosure may employ aShack-Hartmann wavefront sensor, or may employ a Shack-Hartmann sensorin combination with an interferometer to conduct profilometry of thecornea 2. The Shack-Hartmann wavefront sensor provides information forthe treatment of the cornea 2 by analyzing light emerging from theoptical system of the eye 1 and detecting aberrations of the cornea 2. AShack-Hartmann wavefront sensor employs an array of microlenses of thesame focal length. A light source is directed to create a virtual lightsource near the rear of the eye 1 to provide light for emerging from theeye 1. Each microlens creates a beam focused onto a spot on a focalplane where a photon sensor, e.g., a CCD camera, is placed. Thedisplacement of the spot with respect to a precalibrated position(corresponding to an undisturbed wavefront) is proportional to the localslope of the wavefront emerging from the eye 1. Detecting the spots andintegrating their displacements across the focal plan provides anestimate of the wavefront shape, which is itself an estimate of theshape of the corneal surface 2A of the eye 1.

Other embodiments according to the present disclosure may combine theuse of an interferometer (and a wavefront sensor) with a Scheimpflugcamera, which determines the thickness of the cornea 2, i.e., cornealpachymetry, as well as the thickness of the intraocular lens. Suchembodiments provide data on the anterior as well as posterior segmentsof the eye, enabling a full biomechanical analysis of the eyeparticularly after a treatment such as thermokeratoplasty has beenapplied. Some embodiments may employ a rotating Scheimpflug camera tocapture, for example, 25 or 50 images, to collect data on the anteriorsegment. Alternatively, other embodiments may scan along one plane andthen rotate 90 degrees to scan across another plane to define a gridaccording to which the anterior segment may be analyzed.

Still further embodiments may provide information on the surface of theeye 1 using an interferometer arranged such that the reference beam 614is reflected from the eye 1 at some incident angle, which allows theinterferometer to be sensitive to motion along the bisector of theincident angle. The motion may be due to, for example, dynamicdeformation of the corneal surface 2A of the eye 1. Comparisons betweenmultiple measurements with such an angled interferometer configurationcan also provide information on the surface strain of the eye 1.

The interferometry techniques described above may be employed forreal-time monitoring of cross-linking and may be used withthermokeratoplasty or LASIK surgery. However, these techniques are notlimited to such applications. For example, aspects of the presentdisclosure may be employed to treat keratoconus. In particular, datafrom the interferometer provides a pattern of the keratoconus that canbe used to guide the application of an initiating element, e.g., vialaser scanning and eye tracking technologies, and increase the amount ofcross-linking in desired areas. In general, data from the interferometercan be used by a controller to guide the hardware that generatescross-linking activity. With reference to FIG. 4, in an implementationthe feedback system 400 may comprise an interferometer similar to theinterferometers provided in FIGS. 6A and 6D. In such a configuration,the signal beam 614 can be considered the measurements 402, and the datafrom the interferometer (i.e., the interferograms) can be considered thefeedback information 404.

The interferometry techniques above may also be employed to monitorother procedures that surgically or mechanically modify aspects of theeye 1. For example, when penetrating keratoplasty is used to treat thecornea 2, the biomechanics of the corneal graft can be monitored and thetensioning of the sutures can be monitored in real-time.

Another technique for real time monitoring employs polarimetry tomeasure corneal birefringence and to determine the structure of thecorneal tissue. In particular, the technique measures the structure ofthe corneal tissue by applying polarized light to the corneal tissue.Birefringence describes the effect of some materials to retardtransmitted light polarized along an axis of birefringence of thematerial relative to transmitted light polarized orthogonal to the axisof birefringence. For example, a birefringent material may receive alight signal having components polarized both parallel and perpendicularto the axis of birefringence, and the transmitted light can emerge withone of the components phase delayed relative to the other. In someimplementations, the effect of transmitting linearly polarized lightthrough a birefringent material is to rotate the polarization of thetransmitted light relative to the incoming light, and the amount ofrotation of the polarization can be adjusted by modifying theorientation of the birefringent material. For example, the effect ofsome materials to effectively decompose a light beam into two beams whenit passes through the material that have anisotropic (directionallydependent) structure, can describe the effect of a birefringentmaterial. If the material has a single axis of birefringence, tworefractive indices can be respectively assigned for polarizationsparallel and perpendicular to the axis of birefringence for an arbitraryincoming light signal. The light of one polarization propagates moreslowly through the birefringent structure than light of the otherpolarization and becomes retarded in phase. Thus, parameterscharacterizing birefringence are the axis of birefringence and themagnitude of retardation.

The corneal stroma is anisotropic and its index of refraction depends ondirection. The cornea behaves like a curved biaxial crystal with thefast axis orthogonal to the corneal surface and the slow axis (orcorneal polarization axis) tangential to the corneal surface.Accordingly, a light beam emerging from the living eye after a doublepass through the ocular optics contains information on the polarizationproperties of all ocular structures (except optically inactive humours).In particular, a portion of a light beam which enters the eye and passesthrough the cornea may be reflected at the iris and then pass backthrough the cornea to exit the eye. The light emerging from the eye hasthus completed a double pass of the cornea. Analysis of the portion ofthe light beam reflected from the iris and emerging from the eye canreveal structural information about the cornea 2.

FIG. 7A illustrates the increase in Young's modulus with age and isassociated with cross-linking as demonstrated in: Nathaniel E. KnoxCartwright, John R Tyrer, and John Marshall, Age-Related Differences inthe Elasticity of the Human Cornea. Invest. Ophthalmol. Vis. Sci. Sep.16, 2010; doi:10.1167/iovs.09-4798, the contents of which is hereinincorporated by reference in its entirety. Young's modulus provides ameasure of the elasticity or stiffness of a material. Generally, ahigher value of Young's modulus indicates a greater resistance todeformation under a particular stress load. Young's modulus can becomputed as a ratio of applied stress (i.e., tensile or compressivepressure) to measured strain (i.e., dimensionless measure ofdeformation) of a material, and can be measured experimentally by takinga slope of a graph of stress versus strain for a particular material.Referring to TABLE 1, it has been shown that the stiffening effects ofapplying Riboflavin and UV light to initiate cross-linking appears to beequivalent to the effect of aging to the cornea by more than 500 years.

TABLE 1 Condition Young's Modulus Age (Years) Normal 0.49 80 UVRiboflavin 2.25 600 Glutaraldehyde 3.76 1000

Due to the birefringent nature of the anistropic corneal collagenstructures, light emerging from the eye after a double pass through thecorneal tissues may be less polarized than the incoming light. That is,in a system measuring the polarization properties of light emerging fromthe eye following a double pass through the corneal tissues, theemerging light may include a larger fraction of depolarized light thanthe incoming light. Referring to TABLE 2, a study has shown that theamount of depolarized light emerging from the eye following a doublepass of the corneal tissue generally correlates with the age of thesubjects in the study. See Bueno, J. M. J. Op. A: Pure Appl. Opt. 6(2004), S91-S99, the contents of which is herein incorporated byreference in its entirety. Thus, the degree of polarization may providea measure of corneal stiffness, and thus a measure of cross-linkingactivity. In particular, a lesser degree of polarization (orequivalently, an increased amount of depolarized light) may beindicative of an increased amount of corneal stiffness, and thus beindicative of an increased amount of cross-linking activity.

TABLE 2 Subject Age Degree of Polarization 1 24 0.92 2 27 0.76 3 30 0.804 32 0.77 5 41 0.74 6 67 0.61 7 70 0.67

While the tables illustrate relationships between degree of polarizationand corneal stiffness and age, the information gained from the degree ofpolarization may be used in an implementation apart from a particularsubject's age. For example, a degree of polarization of light emergingafter a double pass through the corneal tissues of a patient's eye canprovide information indicative of a baseline amount of corneal stiffnessbefore commencing an eye therapy treatment. The progress of an eyetherapy treatment can then be checked at intervals by measuringsubsequent degrees of polarization, and, if desired, variable parametersfor controlling the application of the eye therapy treatment can beadjusted according to the corneal stiffness indicated by the subsequentmeasurements of degree of polarization.

FIGS. 7B through 7E provide laboratory set-ups that may be employed tomeasure corneal birefringence and polarization properties of lightemerging after a double pass through the corneal tissues. Any of theset-ups and systems provided in FIGS. 7B through 7E may be coupled to ananalysis system adapted to analyze obtained information indicative ofthe polarization properties of the cornea 2. The analysis of theinformation may be carried out by, for example, solving for a Muellermatrix describing the optical effect of the corneal tissue on the lightreflecting from the iris 5. Collectively, the measurement and analysissystems for measuring the corneal birefringence of the corneal tissuesmay be referred to as a corneal polarimetry system. With additionalreference to FIG. 4, the feedback system 400 may comprise a cornealpolarimetry system. Information indicative of the polarizationproperties of the cornea 2 obtained by any of the systems illustrated inFIGS. 7B through 7E may provide the measurements 402. In particular, theintensity of light (e.g., the intensity detected by the CCD camera 760in FIGS. 7B through 7E) after completing a double pass through thecornea 2 may comprise the measurements 402. The degree of polarizationcomputed by the analysis system of the corneal polarimetry system maycomprise the feedback information 404, which is then passed to thecontroller 120. The controller 120 may be adapted to analyze thefeedback information 404 and provide the command signals 406 to thelight source 110. As previously discussed, the controller 120 may befurther adapted to provide the command signals 406 to additionalcomponents to control the amount and degree of cross-linking activitybeing initiated in the cornea 2.

Once the information indicative of the polarization of the cornea 2 hasbeen gathered by one of the measurement systems illustrated in FIGS. 7Bthrough 7E, the birefringence can be calculated. For example, withreference to FIG. 7B, the three images of the pupil's plane recordedaccording to the three independent polarization states of the analyzercan be used to provide independent variables to solve the Mueller-Stokesmatrix with retardation A and azimuth a (fast axis).

Referring to FIG. 7B, an approach for calculating birefringence using acorneal polarimetry system is shown. See Bueno J. M., et al. AppliedOptics (2002), v. 41, 116-124, the contents of which are incorporatedentirely herein by reference. The corneal polarimetry system shown inFIG. 7B includes a laser source 710, which can be a 633 nm He—Ne laser.The laser source 710 illuminates the eye 1, and light reflected form theiris 5 after a double pass through the corneal tissue is passed througha liquid-crystal modulator (“LCM”) 730. The LCM 730 may be an LCMprovided by Meadowlark Optics, such as the HEX69. After passing throughthe LCM 730, the light is focused by an objective lens 740 onto animaging plane of a camera 760. The camera 760 may include a CCDdetector. The controller 120 may send and receive signals to both thecamera 760 and the LCM 730 and may be adapted to analyze the intensityinformation provided by the camera 760 in combination with differentpolarization settings of the LCM 730 to determine the birefringence ofthe cornea 2. In addition, the controller 120 may receive signals from areference detector (“RD”) 762 to account for brightness fluctuations inthe laser source 710.

The polarimetry system of FIG. 7B further includes a beam splitter 712for splitting the output of the laser source 710 toward the RD 762, withthe rest continuing on toward the spatial filter 714. The spatial filter714 is provided to filter and expand the output of the laser source 710,and may include a microscope objective and a pinhole. The filtered andexpanded light is then directed toward a first lens 716 to collimate thebeam. The beam then passes through an aperture 718, which controls thesize of the beam. The aperture 718 may have a diameter of 12 mm. Theoutput of the aperture 718 is then passed through a linear polarizer720, which is oriented with its transmission axis of polarization at a45° to a horizontal orientation. The beam is then split again by asecond beam splitter 722, which reflects the beam toward the eye 1. Someof the light then completes a double pass of the cornea 2, withreflection at the iris 5. The reflected light then emerges back throughthe cornea 2, and half passes through the second beam splitter 722 to bedirected toward the camera 760. A black diffuser 728 is also provided toreduce undesirable reflection and scattering from the portions of thebeam that are directed to the black diffuser 728 by the second beamsplitter 722. Lenses 724, 726 conjugate the pupil plane of the eye 1with the LCM 730, which may be, for example, 15 mm in diameter. A secondlinear polarizer 732 is placed behind the LCM 730, and is orientedparallel to the linear polarizer 720. The combination of the LCM 730 andthe second linear polarizer 732 act as a polarization state analyzer(“PSA”). The objective lens 740 then focuses the beam on an imagingplane of the camera 760.

The LCM 730 may be oriented with a fast axis in a vertical orientation.When driven with appropriate voltages by the controller 120, which canbe defined, for example, during a calibration of the system shown inFIG. 7B, the LCM 730 may produce three completely independentpolarization states. A series of three images may then be obtained, witheach image indicative of the intensity of light detected by the camera760 in one of the three different polarization states. Each pixel of theimages corresponds to an area of the pupil plane. The intensitiesdetected by the camera 760 of the different polarization states provideinformation for solving the Mueller matrix of a birefringent sample withretardation Δ and fast axis orientation a according to theMueller-Stokes formalism, the details of which are provided elsewhere.See, e.g., Bueno J. M., et al. Applied Optics (2002), v. 41, 116-124.

The position of the eye 1 may be stabilized by a bite plate 770 mountedon a three axis micrometric positioner 772. When a subject/patient bitesdown on the bite plate 770, the position of the subject's head isstabilized. Moving the bite plate 770 using the micrometric positioner772 controls the position of the subject's eye 1.

In a system where the corneal polarimetry system provided in FIG. 7B isintegrated into the feedback system 400, the controller 120 may be thesame controller as that shown in FIG. 4. In such a configuration, thecontroller 120 may be adapted to analyze the birefringence informationextracted by the corneal polarimetry system and map the birefringence ofthe cornea 2 to an equivalent amount of cross-linking. The mapping maybe performed according to birefringence information obtained in apreliminary (i.e., pre-treatment) examination of a subject. The mappingmay be calibrated according to additional measures of corneal stiffnessof the subject. Additionally or alternatively, the mapping may beinformed according to average amounts of corneal birefringence observedin subjects with similar characteristics and profiles to the particularsubject being monitored by the corneal polarimetry system. In analternative embodiment, the controller 120 may be replaced by a separatecontroller different from the controller utilized to control thecross-linking activity. The separate controller may be adapted toautomatically send and receive information to and from the controller120, or may be adapted as a completely separate system that provides thebirefringence information to be evaluated by a user, or by a physician.

As previously discussed, FIGS. 7C, 7D, and 7E provide alternativeconfigurations of corneal polarimetry systems useful for detectinginformation indicative of the corneal birefringence. Details of theconfigurations in FIGS. 7C through 7E may be found in Bueno, J. M. J.Op. A: Pure Appl. Opt. 6 (2004), S91-S99; Richert M., et al. EPJ Web ofConferences 5 (2010), 1-5; Knighton R. W and Huang, X. R. Invest. Opt.Vis. Sci. 43 (2002), 82-86, respectively, the contents of which areincorporated entirely herein by reference.

With reference to FIG. 7C, the laser source 710 may be a collimatedinfrared laser beam with 780 nm wavelength and 1.5 mm in diameter. Thelinear polarizer 720 may be oriented to vertically polarize the lightfrom the laser source 710. The polarized light is then directed by thesecond beam splitter 722 to complete a double pass of the cornealtissues and collimated by the lenses 724, 726. The lenses 724, 726 maybe achromatic doublets. The beam is then passed through an analyzerunit, which includes a rotatory retarder 734 and a vertical polarizer736. An aperture 738 limits the size of the beam to 5 mm, and theobjective 740 focuses the beam on the imaging plane of the camera 760.Rotating the rotatory retarder 734 provides different polarizationstates of the analyzer unit. To extract the birefringence information ofthe cornea 2, the analyzer unit may be adapted in four independentpolarization states and images may be recorded with the camera 760 ineach orientation. The images thus obtained can then be analyzed toextract the birefringence information. For example, the four independentpolarization states may correspond to orientations of the rotatoryretarder 734 with the fast axis at −45°, 0°, 30°, and 60°.

Either of the corneal polarimetry systems provided in FIG. 7B or 7C mayoptionally further include a video camera to control the correctpositioning of the subject's eye 1 by use of the micrometric positioner772. The additional video camera can be adapted to be connected to acontroller (such as the controller 120) which automatically detects thelocation of the eye 1 and corrects the position of the eye 1 byadjusting the micrometric positioner 772, which moves the subject's headthrough the bite plate 770. Alternatively, the video camera can beadapted to display the video feed of the eye 1 on a display and anoperator can use a manual method of manipulating the micrometricpositioner 772 according to the displayed video of the eye 1. Forexample, the video feed of the eye 1 may be superimposed on a target orannulus, and an operator may adjust the micrometric positioner 772 witha joystick to maintain the eye 1 in a desirable location relative to thevideo feed.

Alternatively or additionally, the corneal polarimetry system can bemounted on a motorized system and can be adapted to move automaticallyinstead of, or in addition to, the micrometric positioner 772 moving theeye 1.

FIG. 7D schematically illustrates a further configuration of a cornealpolarimetry system arranged in a backscattering configuration. Thecorneal polarimetry system of FIG. 7D includes the laser source 710,which may be a Nd-Yag doubled continuous laser from Spectra Physics thatoperates at 532 nm. A linear polarizer 751 vertically polarizes thelight from the laser source 710. The linearly polarized light is thenpassed through two nematic liquid crystals 752, 753 oriented with theirfast axis indicated by the arrows in FIG. 7D having angles θ₁ and θ₂with the orientation of the linear polarizer 751, respectively. Thelinear polarizer 751 and the two nematic liquid crystals 752, 753 may beconsidered a polarization state generator. The two nematic liquidcrystals 752, 753 act as adjustable retardance elements. The beam maythen optionally be passed through a spatial filter 754. The beam thencompletes a double pass the corneal tissue of the eye 1, and isreflected toward a polarization state analyzer. The polarization stateanalyzer includes the same components as the polarization stategenerator, but the beam passes through in reverse order. The beam isthen focused by the objective lens 740 to an imaging plane of the camera760. The values of the orientation and retardance of each of theretardance elements 752, 753 are chosen in order to minimize thepropagation of errors from intensities to the calculus of Muellermatrices. Similar to the analysis of the corneal polarimetry systemsalready discussed, the Mueller matrix of the corneal tissue is obtainedby successively generating four linearly independent states ofpolarization and by analyzing the backscattering field projected alongthe four linearly independent states.

The corneal polarimetry system having a backscattering configuration ofFIG. 7D may be adapted with an angle of approximately 10° between theinput beam and the output beam, and the laser source 710 may be, forexample, approximately 1.5 m from the cornea 2.

FIG. 7E schematically illustrates yet another configuration of a cornealpolarimetry system useful in extracting birefringence information of thecorneal tissue. The corneal polarimetry system of FIG. 7E includeslight-emitting diode (“LED”) 780. The LED 780 can have a peak wavelengthof 585 nm and can be oriented 7.1° below the optic axis of the cornea 2.Light reflected from the poster surface of the cornea 2 formed theso-called fourth Pukinje image (P_(IV)), which is a small, invertedimage of the LED. Identical achromatic collimating lenses 784, 786magnify the Pukinje image and focus the image on the imaging plane ofthe camera 760. In an implementation, the camera 760 can be replaced byan eyepiece for a user to look through and observe the cornea 2.Rotating linear polarizers 781, 782 and linked to a common shaft 783 andare oriented with their axis of polarization perpendicular to oneanother. Thus, light from the LED 780 polarized by the first linearpolarizer 781 is blocked by the second linear polarizer 782 unless thelight has undergone a change in polarization.

At most polarization orientations, the double-pass through the cornealtissue converts the light emitted from the LED 780 having a polarizationoriented according the first linear polarizer 781 to an ellipticalpolarization state. A Berek variable retarder (“BVR”) 785 is located inthe collimated beam between the collimated lenses 784, 786. The BVR maybe acquired from New Focus of Santa Clara, Calif., and may include atiltable, rotatable plate of MgF₂. The BVR 785 can be adjusted inazimuth and retardance to cancel the effect of birefringence during adouble pass through the corneal tissue. Estimates of the cornealbirefringence may be obtained by the corneal polarimetry system shown inFIG. 7E by first setting the BVR 785 to zero retardance and observingthe Pukinje image. Then, the BVR 785 is rotated until the Pukinje imagedisappears. The amount of rotation of the BVR 785 required to cancel thePukinje image provides an indication of the amount of birefringenceassociated with the corneal tissue 2.

The angle of illumination is an important aspect in the techniquesdirected to measuring birefringence in the cornea 2, because it affectsthe observed birefringent pattern. Accordingly, in one embodiment, thepolarized illumination of the eye may be varied from converging to meetthe radius of curvature of the cornea 2 to providing a collimated beam.By taking images of birefringence as the angle of light is varied, onecan obtain a quantitative measure of the birefringence as a function ofillumination angle and de-convolve the arrangement of lamina, inaddition to obtaining a measure of central corneal birefringentretardation. Advantageously, this approach uses the angle variation todifferentiate anomalies in the stroma more effectively.

Furthermore, it is understood that the concepts described herein arecapable of varying combinations: birefringence analysis (i.e., cornealpolarimetry) only; interferometry analysis only; corneal topographyanalysis only; a combination of interferometry and corneal topographyanalysis; a combination of birefringence, interferometry, and cornealtopography analysis; and so on. For example, because the beam from theinterferometer converges to meet the radius of curvature of the cornea,this technique may be combined with the birefringence techniquedescribed above.

FIG. 8A illustrates a configuration utilizing multiple slit lamps toperform corneal topography and pachymetry. The multiple slit lampconfiguration may also provide targeting information to implementationsof the feedback system 400. The multiple slit lamp configuration shownin FIG. 8A includes four slit lamps 802, 804, 806, 808. Each of the slitlamps 802, 804, 806, 808 may be similar to a conventional slit lampemployed in the field of optometry and ophthalmology to examine apatient's eye and to diagnose conditions existing in the layers of theeye. Each of the slit lamps may be adapted to illuminate a portion ofthe cornea 2 with light emerging from a slit. The slit may be anaperture having a narrow dimension and a broad dimension. While thenarrow dimension is finite, the light emerging from the slit lamp may beapproximately considered as a sheet of light, which illuminates a planeof the cornea 2. The four slit lamps 802, 804, 806, 808 may be orientedoff-center from the optical axis of the cornea 2, and may be orientedwith each at 45° with respect to the eye 1. Furthermore, the four slitlamps may be positioned such that they are equally spaced around the eye1.

The first slit lamp 802 may be positioned above the eye 1 and may directa sheet of light downward at 45° with respect to the eye 1. The secondslit lamp 804 may be positioned to the left of the eye 1 and may directa sheet of light rightward at 45° with respect to the eye 1. The thirdslit lamp 806 may be positioned below the eye 1 and may direct a sheetof light upward at 45° with respect to the eye 1. The fourth slit lamp808 may be positioned to the right of the eye 1 and may direct a sheetof light leftward at 45° with respect to the eye 1. In the schematicillustration provided in FIG. 8A, the second slit lamp 804 is positionedfurther into the page than the first slit lamp 802 and the third slitlamp 806. The fourth slit lamp 808 is positioned further out of the pagethan the first slit lamp 802 and the third slit lamp 806.

The intensity pattern created by the multiple slit lamps illuminatingcornea 2 is directed by the corneal imaging optics 810 to the camera860. Intensity patterns detected by the camera 860 are then analyzed bythe controller 120 to extract corneal topography and pachymetryinformation. An illustrative schematic of an example intensity patterncreated by the four slit lamp configuration is provided in FIG. 8B. Thefour slit lamps illuminate four curved lines on the cornea 2. The shapeand thickness of the pattern observed on the cornea 2 providesinformation indicative of the shape of the corneal surface (i.e.,corneal topography) and the thickness of the cornea 2 (i.e., cornealpachymetry). The thickness of the sheets of light observed with thecamera 860 provide an indication of the corneal thickness when theprecise parameters of the slit lamp orientation and position are known,including the thickness of the aperture of the slit lamps 802, 804, 806,808. As the cornea 2 moves in and out relative to the position of themultiple slit lamps, the illumination pattern observed in the camera 860changes as the sheets of light emitted from the slit lamps scan over thesurface of the cornea 2. As the eye 1 moves relative to the slit lamps,the four curved lines sweep out a grid on the cornea 2. The curvature ofthe lines provide information indicative of the three dimensionalprofile of the eye surface. As the eye moves in and out with respect tothe slit lamps 802, 804, 806, 808, a complete three dimensional profileof the corneal surface may be extracted.

According to an aspect of the present disclosure, the light reflectedfrom the cornea 2 toward the corneal imaging optics 810 includes lightreflected from the corneal surface (i.e., the anterior surface) and fromthe posterior surface of the cornea 2. With reference to FIG. 8B, in animplementation where the slit lamp 802 is oriented above the eye 1 andis directing a sheet of light downward toward the eye 1, the cornea 2 isilluminated with a line 830 having a top edge 831 and a bottom edge 832.The top edge 831 describes the anterior surface of the cornea 2, and thebottom edge 832 describes the posterior surface of the cornea 2.Similarly, other lines on the cornea have an edge closer to thedirection of the associated slit lamp (a proximate edge), and an edgefurther from the direction of the associated slit lamp (a distal edge),and the proximate edge describes the anterior surface of the cornea 2while the distal edge describes the posterior surface of the cornea 2.As some light is reflected from posterior (internal) surface of cornea,the light emerging from the cornea 2 and directed toward the camera 860includes information on the position of the posterior surface andtherefore the thickness of the cornea 2. The emerging light may alsoexperience some spreading due to the diffusive optical characteristicsof the corneal tissue. Ray tracing may also be employed to trace linesfrom slit lamps (e.g., the slit lamp 802) to the camera 860 to providean estimate of anterior and posterior surfaces of cornea 2, and thus theshape and thickness of the cornea 2 at multiple locations may beextracted. By defining the shape and thickness of the cornea 2 atmultiple locations, a three-dimensional profile of the cornea 2 may bedetermined. Using the camera 860, the surface estimates from themultiple slit lamp configuration may be matched to corneal surfaceestimates from an interferometry system (e.g., the interferometersystems of FIGS. 6A, 6D) to provide an even better estimate of the fullcorneal topography.

By providing a three dimensional profile of the cornea 2, the controller120 can determine the center position of the cornea 2. The controller120 can determine the center position by, for example, determining theapex of the three dimensional profile of the cornea surface. Thedetermined center position may then be used in conjunction withadjustable optical and mechanical components to align any of theimplementations of the feedback system 400 previously discussed.

The multiple slit lamp configuration illustrated in FIG. 8A alsoincludes a distance measurement system 670 for determining the distancebetween the multiple slit lamps 802, 804, 806, 808 and the eye 1. In aconfiguration, the distance (or information indicative of the distance)is passed to the controller 120. The controller 120 uses the distanceprovided by the distance measurements system 670 in combination with theimages from the camera 860 to get the radius of curvature of the eye 1,and thus the optical power of the eye 1. The distance measurement canalso allow for scaling the images observed on the camera 860. Thedistance measurement system 670 may be implemented by two camerasfocusing on the surface of the cornea 2, but oriented at an anglerelative to one another, and separated by a known distance, such thatthe angle between the orientations of the two cameras when both arefocused on the eye 1 provides an estimation of the distance according tostandard trigonometric analysis. The distance measurement system 670 maybe implemented as a high resolution camera capturing images from a knownposition. The high resolution camera may be oriented at approximately90° to the optical axis of the eye 1, such that the edge of the eye 1can be mapped to a pixel location of the high resolution camera, whichcorresponds to a distance from the slit lamps 802, 804, 806, 808. Inaddition, the distance measurement system 670 may be adapted accordingto an active ranging technique which uses reflected signals correlatedwith reference signals to measure time delays, such as a doppler,ultrasound, or optical ranging system.

Additionally, in a configuration where the positions of the slit lamps802, 804, 806, 808 are well known, the distance may be estimateddirectly from the slit lamps, camera, and optical elements illustratedin FIG. 8A. Such a distance measurement may be performed by finelyadjusting the position of the eye (e.g., via a positioning systemmounted to a bite plate or head restraint similar to the micronometricpositioner 772 shown in FIGS. 7B and 7C) until the intensity patternobserved by the camera 860 reflects a characteristic pattern (e.g., across centered on the apex of the cornea 2 formed by an overlap betweenthe light of the upper and lower slit lamps 802, 806, and an overlapfrom the light of the side slit lamps 804, 808) that is indicative of aparticular known distance. The position of the eye 1—or the position ofthe slit lamps and associated optics—may then be adjusted by known stepsrelative to the known distance as desired.

FIG. 8B schematically illustrates an image of the cornea 2 detected bythe camera 860 in a configuration utilizing four slit lamps.

FIG. 8C illustrates an exemplary configuration of the bite plate 770 forstabilizing a patient's eye 1 during treatment and evaluation. The biteplate 770 includes a coupling 850 for connecting the bite plate 770 toan external component, such as a stationary rigid member or a memberadapted to be moved by the micrometric positioner 772 of FIGS. 7B and7C. With reference to FIG. 8C, an implementation of the bite plate 770also includes a deformable material 840 distributed generally in a shapesuitable for a user to bite on to. Alternatively, the bite plate 770 maybe implemented as a bar (i.e., a bite bar). In an implementation,aspects of the bite plate 770 may resemble a protective mouth guard, adental bite plate or bite tray, or a similar device. The bite plate 770desirably fixes the location of a subject's head, and thereby fixes thelocation of the subject's eye 1, and can be replaced and/or supplementedby additional mechanical components adapted to restrain a subject's head(e.g., head restraint device(s)) and thereby fix the position of the eye1. In implementations, the bite plate 770 and/or additional mechanicalcomponents for restraining a subject's head may be incorporated in thefeedback systems (such as the exemplary interferometer systems describedin connection with FIGS. 6A and 6D or the polarimetry systems describedin connection with FIGS. 7B through 7E) or incorporated in cross-linkingactivation systems (such as the delivery system 100 described inconnection with FIG. 1). By maintaining a subject's head (e.g., apatient's head) in a rigid configuration with respect to the variouscross-linking activation systems and feedback systems described herein,the application of cross-linking and/or the monitoring of cross-linkingactivity can be more accurately performed.

With reference to the interferometer configurations shown in FIGS. 6Athrough 6E, to maximize the fringe contrast of the interferometer,aspects of the present disclosure may employ a positioning mechanismthat fixedly positions the eye 1 and/or patient's head relative to theinterferometer. The measurements of the deflections of the cornealsurface 2A are more accurate when the patient's head is absolutelyregistered over several cardiac cycles. In one embodiment, the patientbites onto a fixed bite plate (such as the bite plate 770 illustrated inFIG. 8C) that minimizes motion of the patient's head while the imagesare taken by the interferometer. The bite plate 770 may be disposableand formed from a moldable material, e.g., a gel, soft plastic, aheat-moldable material, or the like. The bite plate 770 may also containan RFID chip to monitor usage or to allow access to different diagnosticsoftware modules. With the bite plate 770, even if the patient rotateshis or her eyes, the head (skull) does not shift. As such, the rotationof the saccadic eye movements can be nulled out, e.g., by an algorithm,as a tilt in the direction of the motion. Additionally or alternatively,a chinrest and/or headrest may be employed to maintain cranial fixationand allow for the measurement of multiple frames over time.

The corneal polarimetry systems illustrated in FIGS. 7B through 7E, aswell as other implementations of the feedback system 400 may alsoutilize the bite plate 770 to stabilize the patient's eye 1.Additionally, some embodiments may employ a visible fixation lightsource or object to help the patient align his or her eye relative tothe interferometer. This visible fixation light source or object may beincorporated into the interferometer.

Furthermore, a camera may be employed to assist in aligning theinterferometry system. The camera may be incorporated within theinterferometer and may operate similar to the video camera 510 in FIG.5A. The camera may be coaxially or non-coaxially aligned with theinterferometer. The camera may also be employed to capture images thatcan be used for repeated future alignment. Additionally oralternatively, the camera may be employed for achieving alignment forsecondary systems or procedures that are combined with the use of theinterferometer. Additional mechanical, optical and or electrical controlsystems for course and fine alignment and adjustment of theinterferometer to the corneal surface 2A may be employed, such as bymanipulation of the positioning motors 617 described in connection withFIG. 6D.

FIG. 9A provides a flowchart for activating the cross-linking agent 130in a staged procedure according to an aspect of the present disclosure.It is understood that the application of the cross-linking agent 130 andthe activation of the cross-linking agent 130 described above may occurin a staged procedure. Referring to FIG. 9A, in step 902, heat isapplied in a thermokeratoplasty treatment or LASIK surgery is performedto generate structural changes in the cornea 2 and produce a desiredshape change in a treatment zone according to a desired pattern. In step904, a predetermined amount of time passes. The predetermined amount oftime can be, for example, a period of approximately one week and maycorrespond to a period of time between a patient's appointments with adoctor. In one or more steps 906 after the predetermined period of timeof step 904, the changes to the corneal shape, e.g., refraction, arechecked. The changes to the corneal shape can be checked with one ormore of the feedback systems previously described, including a systemfor performing profilometry of the cornea 2, such as the interferometrysystems of FIGS. 6A through 6E or the polarimetry systems of FIGS. 7Bthrough 7E.

The steps 906 may correspond to follow up, e.g., weekly, appointmentswith the patient after the treatment in step 902. When the patient anddoctor are satisfied with the correction in vision in step 908 and it isdetermined the corneal structure is ready to be stabilized bycross-linking, cross-linking is generated in selected areas of thecornea 2 to stabilize the structural changes in steps 210 and 220,similarly to the techniques described in connection with FIG. 2. In somecases, the patient may be treated with a slight over-correction in step902 to account for any reversal that may occur before the cross-linkingis initiated. If necessary, additional treatment may be applied in step902 according to decision step 910 after the treatment zone has beenchecked in step 906. It is noted that the staged procedure illustratedin FIG. 9A can be employed when cross-linking is activated within thetreatment zone, or outside the treatment zone as described herein.

FIG. 9B provides a flowchart for using an interferometer to conductpre-operative and post-operative examination of the corneal structure tobe treated with LASIK surgery and the cross-linking agent 130. In step912, a pre-operative examination of the eye 1 is performed. Thepre-operative examination may be performed using any of the feedbacksystems discussed above, or may be performed according to conventionaltechniques for determining whether a patient requires LASIK surgery. Instep 914, LASIK surgery is performed to achieve the shape change desiredaccording to the pre-operative examination in step 912. In step 916,dynamic interferometry is employed (such as, e.g., the dynamicinterferometry systems described in connection with FIGS. 6A through 6E)to determine initial structural measurements of the corneal tissue, andparticularly to determine the biomechanical strength or stiffness of thecorneal tissue. In steps 210 and 220, the corneal tissue is treated withthe cross-linking agent 130 to and cross-linking is initiated in thecorneal tissue with the initiating element 222. The determination of thecorneal strength performed in step 916 may be used in part to adjust theamount of cross-linking treatment applied in step 210. In step 918,which may be similar to step 916, the corneal tissue is evaluated againwith dynamic interferometry to determine the biomechanical strength ofthe corneal tissue. In step 920, it is determined if the measure ofcorneal strength or stiffness indicated in step 918 according to thedynamic interferometry system, is sufficient to halt furthercross-linking treatment, or if cross-linking treatment should continueto further strengthen the corneal tissue. According to the outcome ofthe determination made in step 920, the cornea 2 may receive additionalcross-linking therapy by a further application of the initiating element222, and step 918 may be repeated once again. Alternatively, if it isdetermined in step 920 that the cornea 2 has been sufficientlystrengthened by the cross-linking treatment received, then apost-operative examination of the eye 1 is conducted in step 922.

According to one approach, the Riboflavin may be the cross-linking agent130, and may be applied topically to the corneal surface 2A, andtransepithelial delivery allows the Riboflavin to be applied to thecorneal stroma. In configurations where Riboflavin is the cross-linkingagent 130, the application of the cross-linking agent 130 generallysufficiently introduces Riboflavin to mid-depth regions of the cornealtissue where stronger and more stable structure is desired.

Referring to the example embodiment 900C shown in FIG. 9C, thecross-linking agent 925 having a concentration C₁ is applied to thecornea 2 in step 924. The cross-linking agent 925, for example, may beapplied topically to the corneal surface 2A (e.g., the epithelium) ofthe cornea 2. In step 926, a period of time T₁ is allowed to pass.During the period of time T₁, the cross-linking agent 925 diffuses intothe underlying corneal structure according to an exponential gradient.The distribution of cross-linking agent, i.e., concentration ofcross-linking agent 925 at depths at and below the corneal surface 2A,depends at least on the concentration C₁ and the period of time T₁. Theinitiating element 929 is applied to the cornea in step 928 with a powerP₁. As discussed above, in connection with FIG. 2, the initiatingelement 929 may be UV light. The power P₁ of the initiating elementdetermines the extent to which the distribution of cross-linking agent925 is activated. For example, an initiating element applied with apower greater than P₁ may reach greater depths below the corneal surface2A and allow the cross-linking agent 925 to be activated at thesedepths. The power P1 may be selected according to the concentration C₁and the time T₁. The parameters C₁, P₁, and T₁ may be selected toachieve the appropriate amount of cross-linking at desired depths of thecornea 2.

Referring to another embodiment 900D shown in FIG. 9D, the cross-linkingagent 925 with a concentration C₁ is applied to the cornea in step 924.In step 930, the cross-linking agent 925 diffuses into the underlyingcorneal structure during a period of time T₁₁. The initiating element933 with power P₁₁ is then applied to the cornea in step 932. Unlike theembodiment 900C described previously, however, the initiating element isalso applied in one or more additional steps (936, 940) after additionalperiods of time are allowed to pass. For example, during step 934, thecross-linking agent 925 applied in step 924 diffuses farther into theunderlying corneal structure during a second period of time T₁₂. Theinitiating element 933 with power P₁₂ is then applied to the cornea 2 instep 932 to provide further activation of the cross-linking agent 925.As illustrated in FIG. 9D, the initiating element may be applied in anynumber of additional steps. FIG. 9D illustrates the concluding steps 938and 940 where the initiating element 941 with power P_(1a) is finallyapplied after a period of time T_(1a).

In general, each application of the initiating element occurs afterperiods of time T₁₁, T₁₂, . . . , T_(1a), respectively, have passed.During the periods of time T₁₁, T₁₂, . . . , T_(1a), the cross-linkingagent diffuses to increasing depths in the underlying corneal structure,and is incrementally activated with each application of the initiatingelement with powers P₁₁, P₁₂, . . . , P_(1a). In other words, thecross-linking agent is activated as it moves to increasing depths in thecornea 2. The powers P₁₁, P₁₂, . . . , P_(1a) may include anycombination of the same and/or different power values. The periods oftime T₁₁, T₁₂, . . . , T_(1a) may include any combination of the sameand/or different time values. The parameters C₁; P₁₁, P₁₂, . . . ,P_(1a); and T₁₁, T₁₂, . . . , T_(1a) may be selected to achieve theappropriate amount of cross-linking at desired depths of the cornea 2.For example, the periods of time T₁₁, T₁₂, . . . , T_(1a) are selectedto allow the desired amounts of cross-linking agent to reach targetedregions of the cornea 2. Correspondingly, the powers P₁₁, P₁₂, . . . ,P_(1a) are selected so that the desired amount of cross-linking isactivated at these regions.

Referring to yet another embodiment 900E shown in FIG. 9E, theconcentration of C₁ of the cross-linking agent 925 is applied to thecornea 2 in step 924. Similar to the embodiment 900D above, theinitiating element 945 is applied one or more times in step 944 withpowers P₁₁, P₁₂, . . . , P_(1a) after respective periods of time T₁₁,T₁₂, . . . , T_(1a) in step 942. However, in the embodiment 900E,additional concentrations C₂, . . . , C_(n) of the cross-linking agent(947, 953) may be applied to the cornea 2. For example, in step 946, theconcentration of C₂ of the cross-linking agent 947 is applied to thecornea 2. The initiating element 951 is then applied one or more timesin step 950 with powers P₂₁, P₂₂, . . . , P_(2b) after respectiveperiods of time T₂₁, T₂₂, . . . , T_(2b) in step 948. Additionalapplications of the cross-linking agent may be applied until the finalconcentration C_(n) of the cross-linking agent 953 is applied to thecornea 2 in step 952. The initiating element 957 is then applied one ormore times in step 956 with powers P_(n1), P_(n2), . . . , P_(nm) afterrespective periods of time T_(n1), T_(n2), . . . , T_(nm) in step 954.

The concentrations C₁, C₂, . . . , C_(n) may include any combination ofconcentration values. For example, the concentrations C₁, C₂, . . . ,C_(n) may be varied to combine varying distribution gradients andachieve a desired distribution of the cross-linking agent in the cornea2. Each application of the concentrations C₁, C₂, . . . , C_(n) of thecross-linking agent may be activated by a single application of theinitiating element after a period of time. In this case, the values ofa, b, . . . , m in FIG. 9E are equal to 1.

Alternatively, each application of the concentrations C₁, C₂, . . . ,C_(n) may be activated, by a series of applications of the initiatingelement with powers P₁₁, . . . , P_(1a); P₂₁, . . . , P_(2b); andP_(n1), . . . , P_(nm), respectively. In this alternative case, thevalues of a, b, . . . , m in FIG. 9E are greater than 1. However, inother embodiments, the values of a, b, . . . , m may include othercombinations of values. For example, a may equal 1 for a singleapplication of the initiating element 945 for concentration C₁; b mayequal 3 for three applications of the initiating element 951 forconcentration C₂; . . . ; and m may equal 1 for a single application ofthe initiating element 957 for concentration C_(n). Each application ofthe initiating element occurs after respective periods of time T₁₁, . .. , T_(1a); T₂₁, . . . , T_(2b); and T_(n1), . . . , T_(nm) to allow thecross-linking agent to move to increasing depths before being activated.For example, step

The powers P₁₁, . . . , P_(1a); P₂₁, . . . , P_(2b); and P_(n1), . . . ,P_(nm) may include any combination of power values. The periods of timeT₁₁, . . . , T_(1a); T₂₁, . . . , T_(2b); and T_(n1), . . . , T_(nm) mayinclude any combination of time values. The parameters C₁, C₂, . . . ,C_(n); P₁₁, . . . , P_(1a); P₂₁, . . . , P_(2b); and P_(n1), . . . ,P_(nm); T₁₁, . . . , T_(1a); T₂₁, . . . , T_(2b); and T_(n1), . . . ,T_(nm) may be selected to achieve the appropriate amount ofcross-linking at desired depths of the cornea 2. For example, theperiods of time T₁₁, . . . , T_(1a); T₂₁, . . . , T_(2b); and T_(n1), .. . , T_(nm) are selected to allow the desired amounts of cross-linkingagent at concentrations C₁, C₂, . . . , C_(n) to reach targeted regionsof the cornea 2. Correspondingly, the powers P₁₁, . . . , P_(1a); P₂₁, .. . , P_(2b); and P_(n1), . . . , P_(nm) are selected so that thedesired amount of cross-linking is activated at these regions. Ingeneral, varying the combination of concentrations, periods of time, andpower allows the dosage of cross-linking to be spatially tailored.

The combination of concentrations, periods of time, and power may alsobe chosen based in part on feedback information 404 provided by thefeedback system 400 shown in FIG. 4. In addition, the combination ofconcentrations, periods of time, and power may be computed by thecontroller 120 automatically based on the feedback information 404 ormay be manually input by an operator (such as a doctor) after studyingthe feedback information 404. As described above, the feedbackinformation 404 may include images from a video camera (FIG. 5A), froman interferometer (FIG. 6), from a polarimetry system (FIG. 7), or fromany combination of these.

In some embodiments, the cross linking agent may be dissolved in adifferent carrier to promote delivery across the corneal surface 2A. Forexample, the cross-linking agent may be combined in varyingconcentrations with another agent, such as EDTA, benzalkonium chloride,or an alcohol, to promote further delivery across the corneal surface2A.

In other embodiments, a second (neutral) compound may be applied afterany of the concentrations C₁, C₂, . . . , C_(n) of the cross-linkingagent has been applied. The second compound applies a pressure to thecross-linking agent and promotes diffusion of the cross-linking agent todepths of the cornea 2. For example, in FIG. 9F, which provides anembodiment 900F similar to the embodiment 900C, the neutral compound 959is applied in step 958 after the cross-linking agent 925 has beenapplied. However, the neutral compound 959 may be applied at any timeduring the embodiments described herein. For example, the neutralcompound 959 may be applied at a time when diffusion of thecross-linking agent has slowed and needs to be encouraged by the neutralcompound.

In embodiments where the initiating element is UV light, the UV light isapplied according to frequencies (or wavelengths) that correspond withan absorption spectrum of the cross-linking agent, e.g., Riboflavin.Effective absorption of the UV light by the cross-linking agent resultsin activation of the cross-linking agent. The absorption spectrumindicates the amount of absorption exhibited by a given concentration ofcross-linking agent as a function of frequency. An absorption peak inthe absorption spectrum indicates the frequencies at which the UV lightis most effectively absorbed by the cross-linking agent.

In some cases, a spectrophotometer may be employed to apply the UV lightaccording to frequencies within a narrow bandwidth, e.g., approximately0.1 nm resolution. The Beer-Lambert law states that the absorption ofthe UV light is directly proportional to the concentration of theabsorbing material. At sufficiently high concentrations, however, theabsorption spectra show absorption flattening, where the absorption peakappears to flatten because close to 100% of the UV light is alreadybeing absorbed (saturation). The phenomenon of absorption flattening canresult in deviations from the Beer-Lambert law. Such deviation may occurwhen concentrations of cross-linking agent used in the embodiments areexposed to a narrow bandwidth of frequencies, e.g., approximately 0.1 nmresolution. With this narrow bandwidth, saturation occurs and thecross-linking agent reaches a point where no more UV light can beabsorbed.

Alternatively, a light-emitting diode (LED) may be employed to apply theUV light to the cross-linking agent. The bandwidth of frequencies fromthe LED is typically broader than the bandwidth of frequencies from thespectrophotometer. For example, the resolution from the LED may beapproximately 10 nm. The absorption behavior is different when thegreater resolution of the LED is employed. The activation of thecross-linking agent increases with the absorption of additionalfrequencies in the bandwidth. Accordingly, the absorption may becontrolled by increasing the bandwidth of the excitation source (e.g.,the light source 110 in FIG. 1), particularly as a function ofconcentration of the cross-linking agent (or corneal depth as describedpreviously).

Referring to the example embodiment 900G shown in FIG. 9G, thecross-linking agent 961 is applied to the cornea 2 in step 960 with aconcentration C. The cross-linking agent 961, for example, may beapplied topically to the corneal surface 2A of the cornea 2. In step962, a period of time T is allowed to pass. During the period of time T,the cross-linking agent 961 diffuses into the underlying cornealstructure according to an exponential gradient. The distribution ofcross-linking agent, i.e., concentration of cross-linking agent atdepths at and below the epithelium, depends at least on theconcentration C and the period of time T. The initiating element 965 isapplied to the cornea 2 in step 964. As discussed above, the initiatingelement 965 may be UV light. As such, the initiating element 965 in FIG.9G is applied with a power P and a bandwidth B. The power P andbandwidth B with which the initiating element is applied determines theextent to which the distribution of cross-linking is activated.

For example, an initiating element applied with a power greater than Pmay reach greater depths below the corneal surface 2A and allow thecross-linking agent to be activated at these depths. Additionally, aninitiating element applied according to a relatively greater bandwidth Bof frequencies, e.g., from an LED source with approximately 10 nmresolution, results in greater absorption of the UV light and activationof the cross-linking agent. The selection of the power P and bandwidth Bmay depend on the concentration C and the time T. The parameters C, P,T, and B may be selected to achieve the appropriate amount ofcross-linking at desired depths of the cornea.

As described previously with reference to FIGS. 9D and 9E, theinitiating element may be applied in one or more additional steps afteradditional applications of cross-linking agent at one or moreconcentrations and/or after one or more periods of time to allow thecross-linking agent to diffuse into the corneal tissue. In addition toselecting a power for each application of the initiating element, theinitiating element, e.g., UV light, may be applied in the examples aboveaccording to one or more selected bandwidths to control the activationof the cross-linking agent further.

In embodiments where the initiating element is UV light, the UV lightmay be delivered with laser scanning technologies, such as by a laserscanning device 300 described in connection with FIG. 3. For example,embodiments may employ aspects of single photon laser scanning orDigital Light Processing™ (DLP®) technologies. Advantageously, the useof laser scanning technologies allows cross-linking to be activated moreeffectively beyond the surface of the cornea 2, at depths where strongerand more stable corneal structure is desired. In particular, treatmentmay activate cross-linking at a mid-depth region after the cross-linkingagent has moved to this region through diffusion after a period of time.Thus, the application of the initiating element may be applied preciselyaccording to a selected three-dimensional pattern. The power andbandwidth with which the UV light is applied determines in part howdeeply the scanning laser penetrates into the cornea 2, and as such, maybe varied as described previously.

In sum, embodiments stabilize a three-dimensional structure of cornealtissue through controlled application and activation of cross-linking inthe corneal tissue. For example, the cross-linking agent and/or theinitiating element are applied in a series of timed and controlled stepsto activate cross-linking incrementally. Moreover, the delivery andactivation of the cross-linking agent at depths in the cornea 2 dependon the concentration(s) of the cross-linking agent and the power(s) ofthe initiating element.

Furthermore, embodiments provide systems, methods, and devices formonitoring cross-linking activity in the cornea 2 and for monitoring theposition of the cornea 2 and the biomechanical strength of the cornea 2.In embodiments employing any of the incremental approaches to providingeye therapy and activating cross-linking shown in FIGS. 9A through 9G,the incremental steps may be informed, at least in part, by feedbackinformation 404 from the feedback system 400. The various choices in theincremental approach relating to decisions whether to perform additionaleye therapy or cross-linking treatment can be determined partially orcompletely based on the feedback information 404 from the feedbacksystem 400. Additionally, the various choices relating to the properamounts of eye therapy treatment, the concentrations of thecross-linking agent 130, the power, bandwidth, duration, and time delayof the initiating element 222 can each be determined partially orcompletely based on the feedback information 404 from the feedbacksystem 400. As described above, the feedback system 400 may include avideo camera, an interferometer, a polarimetry system, a wavefrontsensor, a Shack-Hartmann sensor, or any combination of these.

In a still further embodiment of the incremental approaches foractivating cross-linking in the cornea 2 and employing the feedbacksystem 400, the controller 120 may automatically determine adjustmentsto parameters (e.g., power, bandwidth, time delay duration,concentration, etc.). Furthermore, the controller 120 may be adapted toactivate the cross-linking agent in incremental steps according to theautomatically determined adjustments without intervention from a user ofthe system. Alternatively, the controller 120 may be adapted toautomatically determine the adjustments and to prompt the user beforeactivating the cross-linking agent before each incremental step, or mayprompt the user after a pre-determined number of incremental activationswith no user intervention. The prompt may display, for example, theproposed parameters with which to apply the next incremental step(s) andallow the user to either approve, deny, or modify the proposedautomatically determined parameters. In an implementation, the promptmay be displayed via a user interface system coupled to the controller120.

Embodiments may apply a mask to ensure that cross-linking activity islimited to selected areas of the cornea. As illustrated in the system1000 in FIG. 10A, a mask 1010 may be positioned over the corneal surface2A before the initiating element 222, i.e., the UV light, from the lightsource 110 is applied. FIG. 10B illustrates an example pattern 1014 forthe mask 1010. In particular, the mask 1010 may be a device similar to acontact lens that is approximately 5 mm in diameter. In an example, azone of structural changes in the cornea 2 may be in an annular pattern.To stabilize the structural changes in the treatment zone, cross-linkingis initiated outside this annular treatment zone. For example,cross-linking may be initiated in areas in the center and/or peripheryof this annular treatment zone. Cross-linking in the areas outside theannular treatment zone provides the corresponding corneal tissue withsufficient strength to stabilize the changes to the new structure in theannular treatment zone. Thus, cross-linking does not have to beinitiated directly in the annular treatment zone to preserve thestructural changes in the annular treatment zone.

As a result, the mask 1010 of FIG. 10A only allows UV light from thelight source 110 to pass to the cornea 2 and the cross-linking agent130, e.g., Riboflavin, is activated in areas outside the treatment zoneaccording to the pattern 1014. In particular, a UV-blocking material1012 helps to define the pattern 1014 on the mask 1010. This UV-blockingmaterial 1012 corresponds with the treatment zone to minimize theactivation of cross-linking within the treatment zone. In alternativeembodiments, the pattern 1014 may be structurally defined as a cut-outfrom the mask 1010. In any case, any UV light from the light source 110outside this pattern 1014 is blocked by the mask 1010. Accordingly, themask 1010 provides more precise activation of the cross-linking agent130. Accordingly, referring to FIG. 2C, the cross-linking agent 130 instep 210 may be applied more broadly to the corneal surface 2A. With theappropriate delivery of the cross-linking agent 130 to the stroma, themask 1010 is applied to the eye 1 in step 215 and the initiating element222 is delivered in step 220 to initiate cross-linking according to thepattern in the mask 1010. In other words, the controlled application ofthe initiating element 222 determines the areas of cross-linking.

Although the mask 1010 is employed to deliver the initiating element 222to the cornea 2 according to a particular pattern, masks may also beemployed in some embodiments to deliver the cross-linking agentaccording to the specific pattern. Thus, the light source 110 of theinitiating element 222 shown in FIG. 10A would be replaced by a sourceof the cross-linking agent 130 (such as the applicator 132 of FIG. 1).

Moreover, although the system 1000 may employ a mask 1010, the devicesemployed for patterned initiation of a cross-linking agent is notlimited to the use of such masks. Embodiments include more generalsystems and methods that activate a cross-linking agent according to aprecise pattern, regardless of the type of device that actually directsthe initiating element to specific areas of the cornea. For example, asshown in FIG. 11A, a system 1100 transforms the initiating element 222,e.g., UV light, from the light source 110 to define a desired pattern1114 as shown in FIG. 11B. In contrast to the system 1000, the system1100 does not block the initiating element 222 from the light source 110from reaching areas outside a pattern. As illustrated in FIG. 11A, anoptical device 1110 receives UV light as a collimated beam 1122 from thelight source 110 and transforms the collimated beam 1122 into thedesired pattern of light 1120. The pattern of light 1120 thus deliversthe UV light to the cornea 2 according to a pattern 1114 thatcorresponds to areas outside the treatment zone. In other words, thepattern 1114 matches the areas where initiation of the cross-linkingagent is desired. In general, any number or types of optical devices,such as lenses, beam-splitters, and the like, may be employed to achievethe desired shape for delivering an initiating element. Moreover, insome embodiments, the use of a mask 1010 as illustrated in FIG. 10A maybe combined with the use of an optical device 1110.

Although cross-linking agents, such as Riboflavin, may be effectivelyapplied to the stroma by removing the overlying epithelium beforeapplication, it has been shown that cross-linking agents can chemicallytransition across the epithelium into the stroma. Indeed, Riboflavin mayalso be delivered to the stroma by applying it topically on theepithelium. Moreover, in some cases, the epithelium may be treated topromote the transition of the cross-linking agent through theepithelium. Accordingly, in the embodiments described herein, no removalof the epithelium is required. Advantageously, this eliminates thepost-operative pain, healing period, and other complications associatedwith the removal of the epithelium.

The use of Riboflavin as the cross-linking agent and UV light as theinitiating element in the embodiments above is described forillustrative purposes only. In general, other types of cross-linkingagents may be alternatively or additionally employed according toaspects of the present disclosure. Thus, for example Rose Bengal(4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) may be employedas the cross-linking agent 130, or as the cross-linking agent deliveredin varying concentrations 925, 947, 953. Rose Bengal has been approvedfor application to the eye as a stain to identify damage to conjunctivaland corneal cells. However, Rose Bengal can also initiate cross-linkingactivity within corneal collagen to stabilize the corneal tissue andimprove its biomechanical strength. Like Riboflavin, photoactivatinglight may be applied to initiate cross-linking activity by causing theRose Bengal to convert O₂ in the corneal tissue into singlet oxygen. Thephotoactivating light may include, for example, UV light or green light.The photoactivating light may include photons having energy levelssufficient to individually convert O₂ into singlet oxygen, or mayinclude photons having energy levels sufficient to convert O₂ intosinglet oxygen in combination with other photons, or any combinationthereof.

As described herein, aspects of the present disclosure may be employedin combination with LASIK surgery. In LASIK surgery, an instrumentcalled a microkeratome is used to cut a thin flap in the cornea. Theflap is peeled back and the underlying corneal tissue is reshaped by theapplication of an excimer laser. After the desired reshaping of thecornea is achieved, the cornea flap is put back in place to complete thesurgery. According to aspects of the present disclosure, a cross-linkingagent is applied to the regions of the cornea treated by the LASIKsurgery.

In one embodiment, the outer surface of the cornea, e.g., in the area ofthe flap, is treated with a cross-linking agent, e.g., Riboflavin, afterthe flap is put back in place. The cross-linking agent is then activatedwith an initiating element. Activation of the cross-linking agent, forexample, may be triggered thermally by the application of microwaves orlight to corresponding areas of the cornea. Cross-linking occurs in thearea of application. Although the cross-linking agent is applied to theouter surface of the cornea, i.e., the epithelium, it has been shownthat cross-linking agents can chemically transition across the outersurface into the underlying corneal tissue, i.e., the stroma. Thus, insome embodiments, the cross-linking agent may be delivered to theunderlying corneal tissue by applying the cross-linking agent topicallyto the outer surface of the cornea. Moreover, in further embodiments,the outer surface may be treated to promote the transition of thecross-linking agent therethrough.

In another embodiment, after the flap is peeled back, inner surfaces ofthe cornea are exposed for the application of a cross-linking agent. Inparticular, the inner surface of the flap as well as the underlyingcorneal tissue are exposed. Therefore, the inner surface of the flapand/or the underlying corneal tissue are treated with a cross-linkingagent. In other words, the cross-linking agent may be applied to (i) theinner surface of the flap only, (ii) the underlying corneal tissue only,or (iii) both the inner surface of the flap and the underlying cornealtissue. The cross-linking agent is then activated with an initiatingelement. Again, activation of the cross-linking agent may be triggeredthermally by the application of microwaves or light. Although theinitiating element may be applied before the flap is put back, theinitiating element additionally or alternatively may be applied to thetreated areas after the flap is put back in place. In this case, theinitiating element can be delivered through the outer surface of thecornea.

According to yet another embodiment, the inner surface of the flapand/or the underlying corneal tissue are treated with a cross-linkingagent after the flap is peeled back. The cross-linking agent is thenactivated with an initiating element. As in the previous embodiment, thecross-linking agent may be applied to (i) the inner surface of the flaponly, (ii) the underlying corneal tissue only, or (iii) both the innersurface of the flap and the underlying corneal tissue. In addition, theouter surface of the cornea, e.g., in the area of the flap, is treatedwith a cross-linking agent after the flap is put back in place. Thecross-linking agent is then activated in step with an initiatingelement. Again, activation of the cross-linking agent may be triggeredthermally by the application of microwaves or light. In a variation ofthis embodiment, the cross-linking agent may be activated with aninitiating element according to a single act, rather than two separateacts. Thus, the initiating element may be delivered in the single actafter the flap is put back in place.

Accordingly, a cross-linking agent may be applied and activated indifferent regions at different points during LASIK treatment. Forexample, the cross-linking agent may be applied to any combination ofthe outer surface of the cornea, the inner surface of the flap, and theexposed underlying corneal tissue. Moreover, specially tailoredconcentrations of cross-linking agent may be applied in combination withvarying levels of initiating element to these regions to achieve theappropriate amount of stability and strength in the cornea.

FIG. 12A illustrates the activation of cross-linking in the regions ofthe cornea treated by the LASIK surgery. After the flap is peeled backin act 1210, inner surfaces of the cornea are exposed for theapplication of a cross-linking agent. In particular, the underlyingcorneal tissue is exposed. Therefore, in act 1230, the underlyingcorneal tissue is treated with a cross-linking agent 1202 after act1220. The cross-linking agent 1230 may be applied, for example, bydripping a measured amount and concentration of the cross-linking agent1202 topically onto the exposed underlying corneal tissue. Thecross-linking agent 1202 is then activated in act 1240 with aninitiating element 1204 while the flap remains peeled back. Activationof the cross-linking agent 1202 may be triggered thermally by theapplication of microwaves or light.

In an example embodiment, Ribloflavin may be applied as thecross-linking agent 1202 to the corneal tissue. In addition, aphotoactivating light, such as ultraviolet (UV) light, may be applied asan initiating element 1204 to initiate cross-linking in the cornealareas treated with Ribloflavin. To achieve optimal results, anappropriate amount of Riboflavin is applied to the targeted regions ofthe cornea and an appropriate amount of UV light is applied to match theapplication of Riboflavin. In some cases, damage to the eye may resultif too much Riboflavin and UV light reach the endothelium. This mayoccur, in particular, if too much time passes between the application ofthe Riboflavin in act 1230 and the application of the UV light in act1240. The passage of time allows the Riboflavin to diffuse more deeplyinto the corneal tissue to the endothelium, and the UV light may reachthe Riboflavin at the endothelium.

Thus, according to aspects of the present invention further illustratedin FIG. 12B, embodiments apply the UV light in act 1240 according to apower and duration that ensure that the application of the UV light doesnot damage the endothelium. The resulting energy determines the depth towhich the UV light penetrates in the corneal tissue. The power andduration are based in part on the amount of time that has passed sincethe application of the cross-linking agent. Because the rate ofdiffusion for a given concentration of the cross-linking agent is known,embodiments can use the time data to calculate how far the cross-linkingagent has traveled into the corneal tissue. Therefore, in act 1232, atime period T₁ is determined from the time t when the cross-linkingagent 1202 is applied in act 1230. Based on this time period T₁, adistance d representing how far the cross-linking agent has traveledinto the corneal tissue is determined in act 1234.

Moreover, the power and duration are also based on the distance that thecross-linking agent and the UV light can travel though the cornea beforereaching the endothelium. This distance generally corresponds with thethickness of the cornea. Therefore, in act 1236, the corneal thickness cis determined. By determining the diffusion distance d of thecross-linking agent and determining the thickness c of the cornea, theappropriate power P and duration T₂ can be determined in act 1238. Theembodiments can apply the UV light to the cross-linking agent in thecornea in act 1240 while preventing damage to the endothelium.

When the cross-linking agent is applied and activated while the cornealflap remains peeled back during LASIK surgery, the amount of cornealtissue through which the cross-linking agent and the UV light can traveldecreases. The risk of damage to the endothelium may be greater duringLASIK surgery. Thus, to ensure that the UV light does not reach theendothelium, act 1236 may determine an “effective” thickness c byadjusting for the fact that the corneal flap is peeled back. Forexample, peeling back the flap may reduce the effective thickness of thecornea to 120 μm, and embodiments may apply the UV light according to apower P and duration T₂ that delivers the UV light to a depth of 100 μm.

Referring to FIG. 13, an embodiment 1300 may employ a corneal treatmentsystem 1310 (e.g., for applying LASIK surgery), a cross-linking agentapplicator 1320 (e.g., for applying Riboflavin to the cornea), and alight source 1330 (e.g., for delivering the UV light to the cornea).Advantageously, aspects of the present invention integrate the operationof the treatment system 1310, the cross-linking agent applicator 1320,and the light source 1330. A controller 1302, e.g., a computer or otherprocessing device, receives input data from the treatment system 1310and the cross-linking agent applicator 1320 and determines parametersfor the operation of the light source 1330. In particular, thecontroller 1302 determines the appropriate power P and duration T₂ forthe controlled light source 1330 to apply light to activate thecross-linking agent.

Referring to FIG. 13, the treatment system 1310 creates a flap that ispeeled back and reduces the cornea's effective thickness c, and thecross-linking agent applicator applies the cross-linking agent at aparticular time t. The controller 1302 receives the effective thicknessc and the time t as input data. Applying the process described in FIG.12B, the controller 1302 then determines the appropriate power P andduration T₂ for the application of the light by the light source 1330.

Although embodiments of the present disclosure may describe stabilizingcorneal structure after treatments, such as LASIK surgery andthermokeratoplasty, it is understood that aspects of the presentdisclosure are applicable in any context where it is advantageous toform a stable three-dimensional structure of corneal tissue throughcross-linking.

The present disclosure includes systems having controllers for providingvarious functionality to process information and determine results basedon inputs. Generally, the controllers (such as the controller 120described throughout the present disclosure) may be implemented as acombination of hardware and software elements. The hardware aspects mayinclude combinations of operatively coupled hardware componentsincluding microprocessors, logical circuitry, communication/networkingports, digital filters, memory, or logical circuitry. The controller maybe adapted to perform operations specified by a computer-executablecode, which may be stored on a computer readable medium.

As described above, the controller 120 may be a programmable processingdevice, such as an external conventional computer or an on-board fieldprogrammable gate array (FPGA) or digital signal processor (DSP), thatexecutes software, or stored instructions. In general, physicalprocessors and/or machines employed by embodiments of the presentdisclosure for any processing or evaluation may include one or morenetworked or non-networked general purpose computer systems,microprocessors, field programmable gate arrays (FPGA's), digital signalprocessors (DSP's), micro-controllers, and the like, programmedaccording to the teachings of the exemplary embodiments of the presentdisclosure, as is appreciated by those skilled in the computer andsoftware arts. The physical processors and/or machines may be externallynetworked with the image capture device(s) (e.g., the CCD detector 660,camera 760, or camera 860), or may be integrated to reside within theimage capture device. Appropriate software can be readily prepared byprogrammers of ordinary skill based on the teachings of the exemplaryembodiments, as is appreciated by those skilled in the software art. Inaddition, the devices and subsystems of the exemplary embodiments can beimplemented by the preparation of application-specific integratedcircuits or by interconnecting an appropriate network of conventionalcomponent circuits, as is appreciated by those skilled in the electricalart(s). Thus, the exemplary embodiments are not limited to any specificcombination of hardware circuitry and/or software.

Stored on any one or on a combination of computer readable media, theexemplary embodiments of the present disclosure may include software forcontrolling the devices and subsystems of the exemplary embodiments, fordriving the devices and subsystems of the exemplary embodiments, forenabling the devices and subsystems of the exemplary embodiments tointeract with a human user, and the like. Such software can include, butis not limited to, device drivers, firmware, operating systems,development tools, applications software, and the like. Such computerreadable media further can include the computer program product of anembodiment of the present disclosure for performing all or a portion (ifprocessing is distributed) of the processing performed inimplementations. Computer code devices of the exemplary embodiments ofthe present disclosure can include any suitable interpretable orexecutable code mechanism, including but not limited to scripts,interpretable programs, dynamic link libraries (DLLs), Java classes andapplets, complete executable programs, and the like. Moreover, parts ofthe processing of the exemplary embodiments of the present disclosurecan be distributed for better performance, reliability, cost, and thelike.

Common forms of computer-readable media may include, for example, afloppy disk, a flexible disk, hard disk, magnetic tape, any othersuitable magnetic medium, a CD-ROM, CDRW, DVD, any other suitableoptical medium, punch cards, paper tape, optical mark sheets, any othersuitable physical medium with patterns of holes or other opticallyrecognizable indicia, a RAM, a PROM, an EPROM, a FLASH-EPROM, any othersuitable memory chip or cartridge, a carrier wave or any other suitablemedium from which a computer can read.

While the present disclosure has been described in connection with anumber of exemplary embodiments, and implementations, the presentdisclosure is not so limited, but rather cover various modifications,and equivalent arrangements.

1. A system for controlling activation of a cross-linking agent appliedto an eye, comprising: a feedback system for providing feedbackinformation indicative of a biomechanical strength of corneal tissue ofthe eye; a controller for receiving the feedback information andautomatically determining an indication of an amount of cross-linking inthe corneal tissue based on the received feedback information; and across-linking activation system for initiating cross-linking in thecorneal tissue according to one or more control signals generated by thecontroller, the one or more control signals generated according to afunction including the determined indication of the amount ofcross-linking in the corneal tissue.
 2. The system of claim 1, whereinthe feedback system comprises an interferometer adapted to interfere abeam of light reflected from a surface of the eye with a reference beamof light reflected from a reference surface, the interfered with beamsof light passing through a polarizing filter and creating an intensitypattern detected by a camera associated with the feedback system, andwherein the feedback information comprises an output from the associatedcamera.
 3. The system of claim 2, wherein the polarizing filter includesa pixelated polarizing filter for simultaneously capturing, via theassociated camera, intensity patterns associated with four polarizationstates.
 4. The system of claim 2, wherein the associated camera isadapted to capture one or more intensity patterns indicative of aplurality of polarized interference patterns in an exposure having aduration less than one millisecond.
 5. The system of claim 2, whereinthe feedback system further comprises a distance measurement system formonitoring a distance between the eye and the interferometer andproviding an indication of the monitored distance to the controller. 6.The system of claim 3, wherein the associated camera is adapted todetect a plurality of intensity patterns and wherein the controller isfurther adapted to: receive the plurality of detected intensitypatterns, determine a plurality of surface profiles of the surface ofthe eye associated with the plurality of detected intensity patternsbased on the plurality of detected intensity patterns and based on themonitored distance, and determine an amount of dynamic deformation ofthe surface of the eye based on the determined plurality of surfaceprofiles.
 7. The system of claim 3, wherein the associated camera isadapted to detect a plurality of intensity patterns and wherein thecontroller is further adapted to: receive the plurality of detectedintensity patterns, determine a plurality of surface profiles of thesurface of the eye associated with the plurality of detected intensitypatterns based on the plurality of detected intensity patterns and basedon the monitored distance, and estimate a volume of tear-film associatedwith the eye based on a difference between a first and second profile ofthe surface of the eye taken from the plurality of surface profiles ofthe surface of the eye.
 8. The system of claim 1, wherein the feedbacksystem is adapted to direct light emitted by a light source to completea double-pass of the corneal optics, direct emerging light that emergesfrom the eye through a polarizing filter, and capture an intensitypattern indicative of a degree of polarization of the emerging light. 9.The system of claim 1, wherein the cross-linking activation systemincludes: a light source for emitting light suitable for activatingcross-linking in the corneal tissue by exciting the cross-linking agentto produce a reactive singlet oxygen from oxygen content in the cornealtissue; and corneal optics for conveying the emitted light to the eyeaccording to the one or more control signals.
 10. The system of claim 7,wherein the corneal optics are operable to convey the emitted light tothe eye according to a non-uniform intensity pattern, and wherein theone or more control signals specify the non-uniform intensity pattern.11. The system of claim 7, wherein the emitted light is conveyed to theeye via a laser scanning device.
 12. The system of claim 7, wherein theemitted light is conveyed to the eye according to a multi-photontechnology.
 13. The system of claim 1, wherein the feedback systemcomprises: one or more lamps emitting narrow slits of light directedtoward the eye, a video camera adapted to monitor the eye, and adistance measurement system adapted to monitor a distance from the eyeto the video camera, wherein the feedback information comprises anoutput of the video camera.
 14. The system of claim 13, wherein the oneor more lamps include: a first lamp and a second lamp are situated aboveand below the eye, respectively, and illuminate the eye with lightemitted at a downward and an upward angle, respectively, and a thirdlamp and a fourth lamp are situated on opposing sides of the eye,respectively, and emit light angled toward the eye from the respectiveopposing sides.
 15. The system of claim 13, wherein the video camera isadapted to begin capturing video images of the eye responsive to the eyeblinking.
 16. The system of claim 1, wherein one or more of the feedbacksystem or the cross-linking activation system includes a head restraintdevice to rigidly align the eye.
 17. The system of claim 16, wherein thehead restraint device comprises a bite plate.
 18. The system of claim 1,wherein the cross-linking agent is Riboflavin or Rose Bengal and thecross-linking activation system includes an ultraviolet light source.19. A method of controllably activating a cross-linking agent applied toan eye, comprising: receiving feedback information comprising electronicsignals output from a feedback system adapted to monitor the eye, thefeedback information indicative of a biomechanical strength of cornealtissue of the eye; automatically analyzing the feedback information todetermine a dosage of light to be applied to the eye; and activating thecross-linking agent by conveying light to the eye according to thedetermined dosage.
 20. The method of claim 19, further comprising:receiving targeting information indicative of an alignment of the eyewith respect to the conveyed light; and automatically adjusting thealignment of the eye with respect to the conveyed light according to thereceived targeting information.
 21. The method of claim 19, wherein thefeedback system comprises an interferometer adapted to interfere a beamof light reflected from a surface of the eye with a reference beam oflight reflected from a reference surface, the interfered with beams oflight passing through a polarizing filter and creating an intensitypattern detected by a camera associated with the feedback system, thefeedback system adapted to allow the associated camera to detect aplurality of intensity patterns, and wherein the feedback informationcomprises the plurality of detected intensity patterns, and wherein theautomatically analyzing the feedback information is carried out by:receiving the plurality of detected intensity patterns, determining aplurality of surface profiles of the surface of the eye associated withthe plurality of detected intensity patterns based on the plurality ofdetected intensity patterns and based on a distance between the surfaceof the eye and the interferometer, and determining an amount of dynamicdeformation of the surface of the eye based on the determined pluralityof surface profiles, the amount of dynamic deformation related to thedosage of light to be applied to the eye.
 22. The method of claim 21,wherein the polarizing filter includes a pixelated polarizing filter forcapturing intensity patterns associated with four polarization states,and wherein intensity patterns associated with four differentpolarizations states are simultaneously detected by the associatedcamera.
 23. The method of claim 21, further comprising: capturing, via aphotosensitive detector, a specular reflection related to the pluralityof intensity patterns detected by the associated camera; analyzing thespecular reflection to determine targeting information associated withthe alignment of the eye with respect to the conveyed light; adjustingthe alignment of the eye with respect to the conveyed light according tothe determined targeting information.
 24. The method of claim 22,wherein targeting information is determined by solving for a centroidposition of the captured specular reflection.
 25. The method of claim22, wherein the targeting information is determined by solving for anenergy distribution of the captured specular reflection.
 26. The methodof claim 22, wherein the adjusting the alignment and the receiving thetargeting information are carried out in real time to stabilize aninitial fringe pattern captured by the associated camera.
 27. The methodof claim 19, wherein the feedback system is adapted to direct lightemitted by a light source to complete a double-pass of the cornealoptics, direct emerging light that emerges from the eye through apolarizing filter, and capture an intensity pattern indicative of adegree of polarization of the emerging light, and wherein the feedbackinformation comprises the degree of polarization.
 28. The method ofclaim 19, wherein the receiving feedback information, the automaticallyanalyzing the feedback information, and the activating the cross-linkingagent are carried out repeatedly.
 29. The method of claim 28, whereinthe repeated carrying out of the activating the cross-linking agent isceased responsive to the biomechanical strength of the cornea indicatedby the feedback information attaining a desired value.
 30. The method ofclaim 19, wherein the light is conveyed to the eye via a laser scanningdevice.
 31. The method of claim 19, wherein the light is conveyed to theeye according to a multi-photon technology.
 32. The method of claim 19,wherein the cross-linking agent is Riboflavin or Rose Bengal and thelight conveyed to the eye is ultraviolet light.
 33. A method foractivating cross-linking in corneal tissue of an eye, comprising:applying a cross-linking agent having a first concentration to the eye;allowing, during a first diffusion time, the cross-linking agent havingthe first concentration to diffuse within the eye; activating thecross-linking agent with a photoactivating light applied according to afirst dose, the first dose specified by a first power and a firstbandwidth; activating the cross-linking agent with the photoactivatinglight applied according to a second dose, the second dose specified by asecond power and a second bandwidth.
 34. The method of claim 33, whereinthe second dose is applied responsive to monitoring the corneal tissuewith a feedback system to determine an amount of cross-linking of thecorneal tissue.
 35. The method of claim 33, further comprising: applyinga cross-linking agent having a second concentration to the eye; andallowing, during a second diffusion time, the cross-linking agent havingthe second concentration to diffuse within the eye.
 36. The method ofclaim 33, wherein the applying, the allowing, and one or more of theactivating the cross-linking agent are carried out repeatedly.
 37. Themethod of claim 33, wherein the first dose or the second dose is appliedsuch that an amount of energy of the photoactivating light is applied toa surface of the eye exceeding 5 J/cm².
 38. A system for activating across-linking agent applied to a cornea of an eye, comprising: a lightsource for emitting photoactivating light; a minor array having aplurality of minors arranged in rows and columns, the plurality ofminors adapted to selectively direct the photoactivating light towardthe eye according to a pixelated intensity pattern having pixelscorresponding to the plurality of mirrors in the mirror array, theplurality of mirrors alignable according to one or more control signals;and a controller for providing the one or more control signals toprogrammatically align the plurality of minors in the array of mirrorssuch that the pixelated intensity pattern emerges from the mirror arrayresponsive to the photoactivating light scanning across the plurality ofminors.
 39. The system of claim 38, further comprising: a camera forcapturing an image of the eye, wherein the captured image of the eyeincludes pixels that are mapped to the pixels corresponding to theplurality of minors.
 40. The system of claim 38, wherein the pluralityof mirrors in the mirror array are selectively alignable to reflectlight from the light source alternately toward the eye or toward a heatsink for controlling an amount of energy of light applied to acorresponding plurality of locations of the eye.
 41. The system of claim38, wherein an intensity of each pixel in the pixelated intensitypattern is proportionate to an amount of time each corresponding minorin the mirror array is aligned to direct the photoactivating lighttoward the eye while the photoactivating light scans across thecorresponding mirror.
 42. The system of claim 38, further comprising: anobjective lens for focusing the pixelated intensity pattern to a focalplane at least partially within the corneal tissue of the eye.
 43. Thesystem of claim 42, further comprising: a camera for capturing videoimages of the eye; a head restraint device for restraining a headassociated with the eye; and a motorized mount adapted to adjust aposition of the objective lens according to a targeting signal, thetargeting signal generated according to the captured video images. 44.The system of claim 38, wherein the pixelated intensity pattern isnon-uniform over the surface of the eye.
 45. The system of claim 38,wherein the cross-linking agent is Riboflavin or Rose Bengal and thephotoactivating light is an ultraviolet laser light source.
 46. Thesystem of claim 38, wherein the light source is an ultraviolet laserlight source and the photoactivating light is sufficient for activatingcross-linking in the corneal tissue by exciting the cross-linking agentto produce a reactive singlet oxygen from oxygen content in cornealtissue of the eye.
 47. A method of activating a cross-linking agentapplied to an eye, comprising: emitting photoactivating light; directingthe photoactivating light to be scanned across a mirror array having aplurality of minors arranged in rows and columns, the plurality ofminors adapted to selectively direct the photoactivating light towardthe eye according to a pixelated intensity pattern having pixelscorresponding to the plurality of mirrors in the minor array, theplurality of mirrors alignable according to one or more control signals;and generating the one or more control signals for programmaticallyaligning the plurality of minors in the mirror array according to thepixelated intensity pattern.
 48. The method of claim 47, furthercomprising: receiving, from a feedback system, feedback informationindicative of an amount of cross-linking in the corneal tissue; andadjusting the one or more control signals based on the feedbackinformation to thereby modify the pixelated intensity pattern applied tothe eye via the minor array.
 49. The method of claim 47, furthercomprising: receiving video images of the eye from a video camera, thevideo images having pixels mapped to the pixels corresponding to theplurality of mirrors.
 50. The method of claim 47, further comprising:conveying the pixelated intensity pattern to the surface of the eye viaone or more optical elements; receiving an image of the eye from acamera; analyzing the received video images to determine targetinginformation; and adjusting an alignment of the eye to the one or moreoptical elements according to the determined targeting information. 51.The method of claim 47, wherein the photoactivating light activatescross-linking in the corneal tissue by exciting the cross-linking agentto produce a reactive singlet oxygen from oxygen content in cornealtissue of the eye.
 52. A system for activating a cross-linking agentapplied to an eye, comprising: a light source for emittingphotoactivating light; and a mask adapted to selectively allow thephotoactivating light to be transmitted therethrough, the regions of themask allowing the photoactivating light to be transmitted defining apattern of activation of the cross-linking agent.
 53. The system ofclaim 52, wherein the mask comprises a circular lens adapted to beplaced on a surface of the eye, the circular lens having a coatingapplied to at least a portion of the circular lens, the coatingsubstantially blocking the photoactivating light from being transmittedthrough the circular lens to the eye.
 54. The system of claim 52,wherein the photoactivating light has sufficient energy to activatecross-linking in the corneal tissue by exciting the cross-linking agentto produce a reactive singlet oxygen from oxygen content in cornealtissue of the eye.
 55. A method of activating a cross-linking agentapplied to an eye, comprising: emitting photoactivating light; anddirecting the photoactivating light to pass through a mask adapted toselectively allow the photoactivating light to be transmittedtherethrough, the regions of the mask allowing the photoactivating lightto be transmitted defining a pattern of activation of the cross-linkingagent.
 56. The method of claim 55, wherein the mask comprises a circularlens adapted to be placed on a surface of the eye, the circular lenshaving a coating applied to at least a portion of the circular lens, thecoating substantially blocking the photoactivating light from beingtransmitted through the circular lens to the eye.
 57. The method ofclaim 56, wherein the coating is applied according to a predetermined orprescribed pattern.
 58. The method of claim 55, wherein thephotoactivating light activates cross-linking in the corneal tissue byexciting the cross-linking agent to produce a reactive singlet oxygenfrom oxygen content in corneal tissue of the eye.
 59. A system formonitoring an eye, comprising: an interferometer comprising: a lightsource for providing a beam of light having a reference polarizationstate, a corneal imaging lens for directing a beam of light from thelight source toward a surface of the eye and collimating light reflectedfrom the surface of the eye, a reference surface for providing areference surface to compare with a surface of the eye, one or more beamsplitters adapted to: split the beam of light and direct a first portionto be reflected from the surface of the eye, and direct a second portionto be reflected from the reference surface, and combine the reflectedfirst portion and the reflected second portion to form a superimposedbeam, a polarizing filter, and a camera for capturing an intensitypattern of the superimposed beam emerging from the polarizing filter;and a controller for analyzing the intensity pattern by: determining aphase offset, for a plurality of points in the captured intensitypattern, between the reflected first portion and the reflected secondportion based on the captured intensity pattern, determining an opticalpath length difference between the reflected first portion and thereflected second portion for the plurality of points from the phaseoffsets determined for the plurality of points, and determining asurface profile of the eye by comparing a profile of the referencesurface to the optical path length differences determined for theplurality of points.
 60. The system of claim 59, wherein the polarizingfilter includes a pixelated polarizing filter for simultaneouslycapturing, via the associated camera, intensity patterns associated withfour polarization states.
 61. The system of claim 59, furthercomprising: a distance measurement system for providing an indication ofa distance between the surface of the eye and the interferometer. 62.The system of claim 59, further comprising: a head restraint device forrestraining a position of a head associated with the eye, the headrestraint device thereby aligning a position of the eye with respect tothe interferometer.
 63. The system of claim 59, wherein the camera isadapted to detect a plurality of intensity patterns in sequence, andwherein the controller is further adapted to: receive the plurality ofdetected intensity patterns, determine a plurality of surface profilesof the surface of the eye associated with the plurality of detectedintensity patterns, and determine an amount of dynamic deformation ofthe surface of the eye based on the determined plurality of surfaceprofiles.
 64. The system of claim 59, further comprising aphotosensitive detector for capturing a specular reflection of a fringepattern of the superimposed beam, and wherein the controller is furtheradapted to: analyze the captured specular reflection and solve for acentroid position of the captured specular reflection, determine anamount of adjustment desirable between an alignment of theinterferometer and the eye, and provide alignment control signals to amotorized adjustment device adapted to align the interferometer with theeye in real time.
 65. The system of claim 64, further comprising: a headrestraint device for restraining a position of a head associated withthe eye, the head restraint device thereby aligning a position of theeye with respect to the interferometer.
 66. The system of claim 65,wherein the head restraint device comprises a bite plate.
 67. A methodof monitoring an eye, comprising: emitting a beam of light from a lightsource having a known polarization; splitting the beam and directing afirst portion to be reflected from a surface of the eye, and directing asecond portion to be reflected from a reference surface; interfering thefirst portion of the beam and second portion of the beam to create asuperimposed beam; directing the superimposed beam through a polarizingfilter; capturing an intensity pattern of the superimposed beam emergingfrom the polarizing filter; analyzing the captured intensity pattern todetermine a surface profile of the surface of the eye.
 68. The system ofclaim 67, wherein the polarizing filter includes a pixelated polarizingfilter for simultaneously capturing, via an associated camera, intensitypatterns associated with four polarization states.
 69. The method ofclaim 67, wherein the analyzing the captured intensity pattern includes:determining a phase offset, for a plurality of points in the capturedintensity pattern, between the reflected first portion and the reflectedsecond portion based on the captured intensity pattern; determining anoptical path length difference between the reflected first portion andthe reflected second portion for the plurality of points from the phaseoffsets determined for the plurality of points; and determining asurface profile of the eye by comparing a profile of the referencesurface to the optical path length differences determined for theplurality of points.
 70. The method of claim 67, further comprising:capturing a plurality of sequential intensity patterns; determining aplurality of surface profiles of the surface of the eye associated withthe plurality of detected intensity patterns; and determining an amountof dynamic deformation of the surface of the eye based on the determinedplurality of surface profiles.
 71. A system for applying a controlledamount of cross-linking in corneal tissue of an eye, comprising: anapplicator adapted to apply a cross-linking agent to the eye; a lightsource for emitting photoactivating light; a targeting system adapted tocreate targeting feedback information indicative of a position of acornea of the eye; a minor array having a plurality of minors arrangedin rows and columns, the plurality of minors adapted to selectivelydirect the photoactivating light toward the eye according to a pixelatedintensity pattern having pixels corresponding to the plurality ofmirrors in the minor array; an interferometer adapted to monitor anamount of cross-linking in the corneal tissue by: interfering a beam oflight reflected from a surface of the eye with a reference beam of lightreflected from a reference surface, and capturing, via an associatedcamera, a series of images of interference patterns due to opticalinterference between the beam of light and the reference beam of light,the series of images being indicative of a plurality of profiles of thesurface of the eye; a head restraint device for restraining a positionof a head associated with the eye, thereby aligning the eye with respectto the interferometer; and a controller adapted to: receive thetargeting feedback information, receive the generated series ofintensity patterns, analyze the generated series of intensity patternsto determine the plurality of profiles of the surface of the eyeassociated therewith, determine an amount of cross-linking of thecorneal tissue based on a dynamic deformation of the surface of the eye,the dynamic deformation of the eye indicated by the plurality ofprofiles of the surface of the eye, and adjust the pixelated intensitypattern according to data comprising at least one of: the targetingfeedback information and the determined amount of cross-linking.
 72. Thesystem of claim 71, wherein the series of images comprise fringepatterns having fringes, the fringes defining continuous bands ofrelatively uniform intensity and corresponding to regions of the surfaceof the eye equidistant from the camera.